Method of treatment for prostatic cancer

ABSTRACT

Disclosed is a new treatment for men with prostatic cancer involving combination therapy of a 5 alpha -reductase inhibitor, i.e., a 17 beta -substituted 4-azasteroid, a 17 beta -substituted non-azasteroid, 17 beta -acyl-3-carboxyandrost-3,5-diene, benzoylaminophenoxybutanoic acid derivative, fused benz(thio)amide or cinnamoylamide derivative, aromatic 1,2-diethers or thioethers, aromatic ortho acylaminophenoxy alkanoic acids, ortho thioalkylacylamino-phenoxy alkanoic acids, pharmaceutically acceptable salts and esters thereof, and particularly finasteride, in combination with an antiandrogen, i.e. flutamide. Pharmaceutical compositions useful for treatment are also disclosed.

This is a continuation of application Ser. No. 08/094,950 filed Dec. 27,1993 now abandoned which is a continuation of application Ser. No.07/846,154, filed Mar. 11, 1992 now abandoned.

BACKGROUND OF THE INVENTION

This invention relates to a new method of treatment for patients, i.e.men having prostatic cancer, which treatment involves a combinationtherapy of administering therapeutically effective amounts of a5α-reductase inhibitor in combination with an antiandrogenic agent.

BACKGROUND OF THE INVENTION

Prostate cancer is the second most common cancer occurring among malesand the third leading cause of cancer deaths in males over 50. Mostprostate cancers exhibit some degree of androgen dependence. Eunuchs donot develop prostate cancer suggesting a hormonal role for prostatecancer. Charles Huggins, et al., established conclusively that androgensplay a pivotal role in prostate cancer and that surgical or medicalcastration of affected men often causes at least temporary regression ofthe tumor. (See Cancer Research 1, pp. 293-297 (1941).)

It is known that testosterone (T) is secreted by the testes and adrenalglands but can undergo a 5α-reductase mediated conversion todihydrotestosterone (DHT) in peripheral sites including the liver, skin,and prostate. DHT is preferentially bound by the nucleus of prostaticcells and so it is generally accepted that DHT, rather than T, is theandrogen required by the prostate for its growth and function.

Finasteride, 17β(N-t-butyl)carbamoyl-4-aza-5α-androst-1-en-3-one wasdeveloped as the culmination of a search for compounds which wouldinhibit 5α-reductase and thus have the potential for being usefulagainst benign prostatic hyperplasia. Finasteride is a 4-azasteroid anda competitive inhibitor of the enzyme. It shows no affinity for theandrogen receptor and so would not be expected to interfere with thebinding and action of T in those tissues, such as muscle, which respondto T.

However, these above studies do not provide information on whetherfinasteride is an effective and safe agent in the treatment of prostaticcancer.

There are several methods described in the prior art for treatingprostatic cancer and related prostatic disorders, for example:

U.S. Pat. No. 4,472,382 (Labrie, et al.), discloses that prostateadenocarcinoma, benign prostate hypertrophy and hormone-dependentmammary tumors may be treated with various LH-RH agonists and thatprostate adenocarcinoma and benign hypertrophy may be treated by use ofvarious LH-RH agonists and an antiandrogen.

U.S. Pat. No. 4,659,695 (Labrie), discloses a method of treatment ofprostate cancer in susceptible male animals including humans whosetesticular hormonal secretions are blocked by surgical or chemicalmeans, e.g., by use of an LH-RH agonist, e.g., [D-Trp⁶, des-Gly-NH₂ ¹⁰]LH-RH ethylamide which comprises administering an antiandrogen, e.g.,flutamide in association with at least one inhibitor of sex steroidbiosynthesis, e.g., aminoglutethimide and/or ketoconazole.

U.S. Pat. No. 3,995,060 (Neri, et al.), discloses methods of preparingcertain antiandrogens including 4'-substituted and 3',4'-disubstitutedanilides, e.g. flutamide, and their use in treating androgen-dependentor androgen-caused disease states, such as prostatic andenocarcinoma,benign prostate hypertrophy, hirsutism, and acne, in mammals, includingman.

U.S. Pat. No. 4,895,715 (Neri, et al.), discloses methods for treatingandrogen-dependent gynecomestia in patients being treated for diseasessuch as benign prostatic hypertrophy involving the combination therapyof an antiandrogen, i.e. flutamide with an antiestrogen, or an aromataseinhibitor.

However, none of these methods suggest or employ a 5α-reductaseinhibitor alone or in combination with another agent.

In addition to DHT, there are other androgens such as testosterone (T)which are also active in the prostate by participating in binding toandrogen receptors. It is known that antiandrogen agents, i.e. thenon-steroidal flutamide, being4'-nitro-3'-trifluoromethyl-isobutyranilide, are effective ascompetitive agents in binding to the androgen receptors, thus blockingthe adverse action of androgens in androgen-dependent disease states.(See U.S. Pat. No. 3,995,060 to Neri, Supra.)

It is further known that, in the early stages of prostatic cancerprostatic tumors are androgen-dependent for growth. One of the mostimportant androgens in this respect is dihydrotestosterone (DHT). Theproduction of DHT in the prostate by the enzymic action of 5α-reductaseon testosterone can be blocked by the use of e.g., 4-aza steroids, as5α-reductase inhibitors, which are known in the art. (See Merck U.S.Pat. No. 4,760,071.) Further, it is believed that testosterone, also anandrogen, may have characteristics required by prostatic tumors.

Thus, the combined effect of a 5α-reductase inhibitor in inhibiting DHTproduction in the prostate and the androgen receptor blocking action ofan antiandrogen, i.e. flutamide, will produce a greater effect onsuppressing the growth, spread and metastasis of prostatic tumors theneither agent by itself.

SUMMARY OF THE INVENTION

By this invention there is provided a method of treating prostaticcancer patients who are in need of such treatment comprising the step ofadministering in combination to such patients therapeutically effectiveamounts of a 5α-reductase inhibitor e.g. a 17β-substituted 4-azasteroid,a 17β-substituted non-azasteroid, 17β-acyl-3-carboxyandrost-3,5-diene,benzoylaminophenoxybutanoic acid derivative, fused benz(thio)amide orcinnamoylamide derivative, aromatic 1,2-diethers or thioethers, aromaticortho acylaminophenoxy alkanoic acids, ortho thioalkylacylamino-phenoxyalkanoic acids, pharmaceutically acceptable salts and esters thereof,and particularly finasteride in combination with an antiandrogen.

BRIEF DESCRIPTION OF THE INVENTION AND PREFERRED EMBODIMENTS

In one preferred aspect, the present invention provides an effectivemethod of treating prostate cancer in patients in need of such treatingby administering therapeutically effective amounts of the antiandrogenin association with a 5α-reductase inhibitor or pharmaceuticalcomposition thereof. The active compounds may be administered togetheror in any order, as discussed hereinafter.

By the term "patients in need of such treating" is meant "male patientswith functioning gonads who are being treated with a 5α-reductaseinhibitor in a therapeutic program designed to combat prostatic cancerand/or benign prostatic hyperplasia (BPH) and are discovered to have astage of cancer in which the prostatic tumors are still androgendependent.

The use of therapeutically effective amounts of the 5α-reductaseinhibitor and the antiandrogen in accordance with this inventioneffectively treats prostatic cancer and is more effective than the useof either agent entirely by itself.

Typical suitable antiandrogens known in the art and useful and includedwithin the scope of this invention include nonsteroidal antiandrogenssuch as the imidazolidines, especially1-(3'-trifluoromethyl-4'nitrophenyl)-4,4-dimethyl-imidazoline-2,5-dione(also called Anandron) described in U.S. Pat. No. 4,097,578;4'-nitro-3-trifluoromethylisobutyranilide (also called flutamide)described in U.S. Pat. No. 3,847,988, hydroxyflutamide described in U.S.Pat. No. 3,875,229 and prodrug forms of hydroxyflutamide; theN-(phenylalkanoyl)aniline derivatives disclosed in U.S. Pat. No.4,386,080; the 3,4-disubstituted-branched-chain acylanilides disclosedin U.S. Pat. No. 4,239,776 (A. T. Glen, et al.) and specifically casodex(Imperial Chemical Industries), which is N-[4-cyano-3-(trifluoromethyl)phenyl]-3-[(4-fluorophenyl)sulfonyl]-2-hydroxy-2-methyl-propionamidedisclosed in U.S. Pat. No. 4,636,505 (H. Tucker).

Representative compounds of the non-steroidal antiandrogens describedabove are the following:

1-(3'-trifluoromethyl-4'-nitrophenyl)-4,4-dimethyl-5-iminoimidazoline-2-one;

1-(3'-trifluoromethyl-4'-nitrophenyl)-4,4-dimethyl-imidazoline-2,5-dione;

ethyl N-(4-nitro-3-trifluoromethylphenyl)-cyclopropylcarbimidate;

ethyl N-(4-nitro-3-trifluoromethylphenyl)-isobutyrimidate;

ethyl N-(4-iodo-3-trifluoromethylphenyl)-isobutyrimidate;

ethyl N-(4-nitro-3-trifluoromethylphenyl)-2.3-dimethyl-butyrimidate;

ethyl N-(4'-nitro-3'trifluoromethylphenyl)-2-methylbutyrimidate;

ethyl N-(4-bromo-3-trifluoromethylphenyl)-isobutyrimidate;

ethyl N-(4-nitrophenyl)-isobutyrimidate;

ethyl N-(4-chloro-3-trifluoromethylphenyl)-isobutyrimidate;

ethyl N-(3-bromo-4-nitrophenyl)-isobutyrimidate;

ethyl N-(3-chloro-4-nitrophenyl)-isobutyrimidate;

N-(4-Nitro-3-trifluoromethylphenyl) isobutyrchlorimidate;

4-Nitro-3-trifluoromethylisobutyrthioanilide;

Ethyl N-(4-nitro-3-trifluoromethylphenyl)-isobutyrimidate;

Methyl N-(4-nitro-3-trifluoromethylphenyl)-2-hydroxyisobutyrimidate;

2-bromo-4'-nitro-3'-trifluoromethylisobutyranalide;

2-methoxy,2-fluoro-2-chloro-3'-trifluoromethylisobutyranilide;

2-iodo-4'-nitro-3'trifluoromethylisobutyranilide;

N-methyl-2-bromo-4'-nitro-3'-trifluoromethylisobutyranilide;

N-ethyl-2-bromo-4'-nitro-3'-trifluoromethylisobutyranilide;

N-propyl-2-bromo-4'-nitro-3'-trifluoromethylisobutyranilide;

N-butyl-2-bromo-4'-nitro-3'-trifluoromethylisobutyranilide;

2-hydroxy-4'-nitro-3'-trifluoromethylisobutyranilide;

3',4'dinitro-2-hydroxyisovaleranilide;

4'-chloro-2-hydroxy-3'-trifluoromethylcyclobutylcarbanilide;

3'-chloro-2-hydro-4'-iodocyclopropylcarbanilide;

3'-bromo-2-hydroxy-3-methyl-4'-nitrovaleranilide;

2-hydroxy-3'-iodo-4'-trifluoromethylisobutyranilide;

2,3-dimethyl-2-hydroxy-3'-methyl-4'-nitrovaleranilide;

3'-acetyl-2,3-dimethyl-2-hydroxy-4'-iodovaleranilide;

3'-acetyl-2,3-dimethyl-2-hydroxy-4'-nitrovaleranilide;

2-hydroxy-3'-methoxy-4'nitroisobutyranilide;

3'-ethyl-2-hydroxy-4'-trifluoromethylisobutyranilide;

2,3-dimethyl-2-hydroxy-4'-nitro-3'-trifluoromethylthiovaleranilide;

4'-chloro-2-hydroxy-3'-propylisobutyranilide;

3'-bromo-2,3-dimethyl-2-hydroxy-4'-trifluoromethylcyclopropylcarbanilide;

2-hydroxy-4'-nitrobutyranilide;

2-hydroxy-3'-nitro-4'-bromoisobutyranilide;

4'-chloro-2-hydroxy-3'-iodoisovaleranilide;

2-bromo-4'-nitrocyclopropylcarbanilide;

2,3-dimethyl-2-hydroxy-3'-propionyl-4'-trifluoromethylbutyranilide;

2,3-dimethyl-2-hydroxy-3'-propionyl-4'-nitrobutyranilide;

2-hydroxy-4'-trifluoromethylisobutyranilide;

2-hydroxy-4'-nitro-3'-trifluoromethylisovaleranilide;

2-hydroxy-2-methyl-4'-nitro-3'-trifluoromethylbutyranilide;

2-hydroxy-3'-4'-dichloroisobutyranilide;

2-hydroxy-3'-4'-diiodoisobutyranilide;

3'-fluoro-2-hydroxy-4'-nitroisobutyranilide;

2-hydroxy-4'-chloro-3'-trifluoromethylisobutyranilide;

2-hydroxy-4'-nitroisobutyranilide;

2-ethyl-2-hydroxy-4'-nitro-3'-trifluoromethylbutyranilide;

3'-bromo-2-hydroxy-4'-nitroisobutyranilide;

2,3-dimethyl-2-hydroxy-4'-nitro-3'-trifluoromethylbutyranilide;

2-hydroxy-N-methyl-4'-nitro-3'-trifluoromethylisobutyranilide;

4'-chloro-2-hydroxy-N-methyl-3'-trifluoromethylisobutyranilide;

4'-bromo-2-hydroxy-3'-trifluoromethylisobutyranilide;

2,3-dimethyl-2-hydroxy-4'-nitro-3'-trifluoromethylbutyranilide;

2-hydroxy-N-methyl-4'-nitro-3'-trifluoromethylisobutyranilide;

2-acetoxy-4'-nitro-3'-trifluoromethylisobutyranilide;

2-methoxy-4'-nitro-3'-trifluoromethylisobutyranilide;

2-valeryloxy-4'-nitro-3'-trifluoromethylisobutyranilide;

2-hydroxy-3'-bromo-4'-nitroisobutyranilide;

2-hydroxy-4'-bromo-3'-trifluoromethylisobutyranilide;

2-acetoxy-4'-bromo-3'-trifluoromethylisobutyranilide;

3'-bromo-2-chloro-4'-nitroisobutyranilide;

2-bromo-4'-nitro-3'-trifluoromethylisobutyranilide;

N-methyl-2-methoxy-4'-nitro-3'-trifluoromethylisobutyranilide;

4'-bromo-2-chloro-3'-trifluoromethylisobutyranilide;

2-chloro-4'-iodo-3'-trifluoromethylisobutyranilide;

2-acetoxy-4'-bromo-3'-trifluoromethylisobutyranilide;

3'-chloro-2-hydroxy-4'-nitroisobutyranilide;

4'-bromo-2-methoxy-3'-trifluoromethylisobutyranilide;

2-chloro-4'-nitro-3'-trifluoromethylisobutyranilide;

2-hydroxy-4'-chloro-3'-trifluoromethylisobutyranilide;

2-hydroxy-4'-nitro-3'-trifluoromethylcyclopropylcarbanilide;

2-hydroxy-4'-iodo-3'-trifluoromethylcyclopropylcarbanilide;

2,3-dimethyl-2-hydroxy-4'-nitro-3'-trifluoromethylbutyranilide;

2-hydroxy-4'-nitro-3'-trifluoromethylisovaleranilide;

4'-bromo-2-hydroxy-3'-trifluoromethylisobutyranilide;

2'-hydroxy-4'-nitroisobutyranilide;

4'-chloro-2-hydroxy-3'-trifluoromethylisobutyranilide;

3'-bromo-2-hydroxy-4'-nitroisobutyranilide;

3'-chloro-2-hydroxy-4'-nitroisobutyranilide;

2-chloro-4'-nitro-3'-trifluoromethyl-cyclopropylcarbanilide;

2-chloro-4'nitro-3'-iodo-3'-trifluoromethylbutyranilide;

2-chloro-4'-nitro-3'-trifluoromethylcyclopropylcarbanilide;

2-chloro-4'-nitro-3'-trifluoromethyl-isobutyranilide;

2-chloro-2,3-dimethyl-4'iodo-3'-trifluoromethylbutyranilide;

2-chloro-4'-nitro-3'-trifluoromethylisovaleranilide;

4'-bromo-2-chloro-3'-trifluoromethylisovaleranilide;

4'-bromo-2-chloro-3'-trifluoromethylisobutyranilide;

2-chloro-4'-nitroisobutyranilide;

2,4'-dichloro-3'-trifluoromethylisobutyranilide;

3'-bromo-2-chloro-4'-nitroisobutyranilide;

2,3'-dichloro-4'-nitroisobutyranilide;

4'-Nitro-3'-trifluoromethyl-2-valeryloxyisobutyranilide;

3,4-dichloro-N-(2-hydroxy-2-p-nitrophenylpropionyl)aniline;

4-nitro-3-trifluoromethyl-N-(2-hydroxy-2-p-nitro-phenylpropionyl)aniline;

4-cyano-3-trifluoromethyl-N-(2-hydroxy-2-p-nitro-phenylpropionyl)aniline;

3-chloro-4-nitro-N-(2-hydroxy-2-p-nitrophenylpropionyl)aniline;

3-chloro-4-methylsulphonyl-N-(2-hydroxy-2-p-nitro-phenylpropionyl)aniline;

4-nitro-3-trifluoromethyl-N-(2-hydroxy-2-p-trifluoromethylphenylpropionyl)aniline;

3-chloro-4-nitro-N-(2-hydroxy-2-p-trifluoromethylphenylpropionyl)aniline;

4-nitro-3-trifluoromethyl-N-(2-p-cyanophenyl-2-hydroxypropionyl)aniline;

4-nitro-3-trifluoromethyl-N-(2-p-fluorophenyl-2-hydroxypropionyl)aniline;

4-nitro-3-trifluoromethyl-N-(2-hydroxy-2-p-methylsulphinylphenylpropionyl)aniline;

3,4-dichloro-N-(2-hydroxy-2-p-methylsulphinylphenylpropionyl)aniline;

3,4-dichloro-N-(2-p-acetylphenyl-2-hydroxypropionyl)aniline;

3,4,5,-trichloro-N-(2-hydroxy-2-p-nitrophenylpropionyl)aniline;

2-chloro-4-nitro-N-(2-hydroxy-2-p-nitrophenylpropionyl)aniline;

N-(2-methoxy-2-p-nitrophenylpropionyl)-4-nitro-3-trifluoromethylaniline;

N-(2-n-butoxy-2-p-nitrophenylpropionyl)-4-nitro-3-trifluoromethylaniline;

4-nitro-3-trifluoromethyl-N-(2-p-nitrophenylpropionyl)aniline;

4-nitro-3-trifluoromethyl-N-(2-hydroxy-2-p-methanesulphinylphenylpropionyl)aniline;

4-nitro-3-trifluoromethyl-N-(2-hydroxy-2-p-methanesulphonylphenylpropionyl)aniline;

4-nitro-3-trifluoromethyl-N-(3-chloro-2-hydroxy-2-p-nitrophenylpropionyl)aniline;

3,4-dichloro-N-(3-chloro-2-hydroxy-2-nitrophenylpropionyl)aniline;

3-chloro-4-cyano-N-(3-chloro-2-hydroxy-2-p-nitrophenylpropionyl)aniline;

3,4-dichloro-N-(2-hydroxy-2-p-methoxycarbonylphenylpropionyl)aniline;

5-methyl-5-p-nitrophenyl-3-(4-nitro-3-trifluoromethylphenyl)oxazolidine-2,4-dione;

3,4-dicyanoisobutyrylanilide;

3,4-dicyano-(2-hydroxy-2-methylpropionyl)anilide;

3,4-dicyano-N-methylisobutyrylanilide;

3,4-dicyano-(2-methoxy-2-methylpropionyl)anilide;

4-cyano-3-trifluoromethyl-(2-hydroxy-2-methylpropionyl)anilide;

3,4-dicyano-(2-acetoxy-2-methylpropionyl)anilide;

3,4-dicyano-(2-hydroxy-2-methylpropionyl)anilide;

3,4-dicyano-(cyclopropanecarbonyl)anilide;

3-cyano-4-nitro-(2-hydroxy-2-methylpropionyl)anilide;

3,4-dicyano-N-methylisobutyranilide;

3,4-dicyano-N-ethylisobutyranilide;

N-butyl-3,4-dicyanoisobutyranilide;

3,4-dicyano-(2-decanoyloxy-2-methylpropionyl)anilide;

3,4-dicyano-(2-hydroxy-2-methylpropionyl)anilide;

3-chloro-4-cyano-N-(3-ethylthio-2-hydroxy-2-methylpropionyl)aniline;

3-chloro-4-cyano-N-(3-ethylsulphonyl-2-hydroxy-2-methylpropionyl)aniline;

4-cyano-3-trifluoromethyl-N-(2-hydroxy-2-methyl-3-phenylsulphonylpropionyl)aniline;

4-cyano-3-trifluoromethyl-N-(3-ethylsulphonyl-2-hydroxy-2-methylproionyl)aniline;

4-nitro-3-trifluoromethyl-N-(2-hydroxy-3-phenylsulphonyl-2-methylpropionyl)aniline;

4-nitro-3-trifluoromethyl-N-(3-ethylsulphonyl-2-hydroxy-2-methylpropionyl)aniline;

3-chloro-4-nitro-N-(2-hydroxy-3-phenylthio-2-methylpropionyl)aniline;

4-nitro-3-trifluoromethyl-N-[2-hydroxy-2-methyl-3-(thiazol-2-ylthio)propionyl]aniline;

4-nitro-3-trifluoromethyl-N-[3-allylthio-2-hydroxy-2-methylpropionyl)aniline;

4-nitro-3-trifluoromethyl-N-(3-p-fluorophenylthio-2-hydroxy-2-methylpropionyl)aniline;

4-nitro-3-trifluoromethyl-N-[2-hydroxy-2-methyl-3-(pyrid-2-ylthio)propionyl]aniline;

4-nitro-3-trifluoromethyl-N-[2-hydroxy-2-methyl-3-(5-methyl-1,3,4-thiadiazol-2-ylthio)propionyl)aniline;

4-nitro-3-trifluoromethyl-N-[2-hydroxy-2-methyl-3-(4-methylthiazol-2-ylthio)propionyl]aniline;

4-nitro-3-trifluoromethyl-N-[2-hydroxy-2-methyl-3-(pyrid-2-ylsulphonyl)propionyl]aniline;

4-nitro-3-trifluoromethyl-N-(3-p-fluorophenyl-sulphonyl-2-hydroxy-2-methylpropionyl)aniline;

4-cyano-3-trifluoromethyl-N-[2-hydroxy-2-methyl-3-(thiazol-2-ylthio)propionyl]aniline;

4-cyano-3-trifluoromethyl-N-[2-hydroxy-2-methyl-3-(pyrid-2-ylthio)propionyl]aniline;

4-cyano-3-trifluoromethyl-N-(2-hydroxy-2-methyl-3-methylthiopropionyl)aniline;

4-cyano-3-trifluoromethyl-N-(3-p-fluorophenylthio-2-hydroxy-2-methylpropionyl)aniline;and

4-cyano-3-trifluoromethyl-N-(3-p-fluorophenyl-sulphonyl-2-hydroxy-2-methylpropionyl)aniline,and the like.

Typical suitable steroidal antiandrogens known in the art includecyproterone,6-chloro-1,2-dihydro-17-(acetyl)-3'H-cyclopropa[1,2]-pregna-1,4,6-triene-3,20-dione,available under the tradename of Androcur from Schering A. G., W.Berlin. See U.S. Pat. No. 3,234,093.

The use of pure antiandrogens such as flutamide is preferred. By theterm "pure antiandrogen" is meant an antiandrogen which is devoid of anyandrogenic, estrogenic, antiestrogenic, progestational,antiprogestational, angonadotrophic or adrenocortical activity.

Typical 5α-reductase inhibitors known in the art include the 4-azasteroids developed by Merck. (See U.S. Pat. No. 4,377,584 to Rasmusson,et al; U.S. Pat. No. 4,220,735 to Rasmusson, et al.; U.S. Pat. No.4,845,104 to Carlin, et al; U.S. Pat. No. 4,760,071 to Rasmusson, etal., which discloses finasteride, being17β-(N-t-butyl)carbamoyl-4-aza-5α-androst-1-en-3-one, known by itstrademark as PROSCAR*; U.S. Pat. No. 4,732,897 to Cainelli, et al.; U.S.Pat. No. 4,859,681 to Rasmusson, et al.; EPO Publn. 0 155 076; EPOPubln. 0 004 949; and EPO Publn. 0 314 189.

Preferred are where the 4-aza steroid has the formula: ##STR1## whereinthe dotted line represents a double bond when present, R¹ and R³ areindependently hydrogen, methyl or ethyl,

R² is a hydrocarbon radical selected from straight or branched chainsubstituted or unsubstituted alkyl, cycloalkyl, or aralkyl of from 1-12carbons or monocyclic aryl optionally containing 1 or more lower alkylsubstituents of from 1-2 carbon atoms and/or 1 or more halogensubstituents,

R' is hydrogen or methyl,

R" is hydrogen or β-methyl,

R'" is hydrogen, α-methyl or β-methyl, and pharmaceutically acceptablesalts or esters thereof.

A preferred embodiment of the compound of formula I applicable in theprocess of our invention is represented by the formula: ##STR2## whereinR¹ is hydrogen, methyl or ethyl, and

R² is branched chain alkyl, cycloalkyl, aralkyl of from 4-12 carbons,

phenyl, optionally substituted by methyl, chloro or fluoro, substitutedor unsubstituted 1-, 2-adamantyl, 1-, 2-adamantylmethyl, 1-, 2- or7-norbornanyl, 1-, 2- or 7-norbornanymethyl.

Representative compounds of the present invention include the following:

17β-(N-tert-amylcarbamoyl-4-aza-5α-androst-1-en-3-one,

17β-(N-tert-hexylcarbamoyl)-4-aza-5α-androst-1-en-3-one,

17β-(N-tert-butylcarbamoyl)-4-aza-5α-androst-1-en-3-one,

17β-(N-isobutylcarbamoyl)-4-aza-5α-androst-1-en-3-one,

17β-(N-tert-octylcarbamoyl)-4-aza-5α-androst-1-en-3-one,

17β-(N-octylcarbamoyl)-4-aza-5α-androst-1-en-3-one,

17β-(N-1,1-diethylbutylcarbamoyl)-4-aza-5α-androst-1-en-3-one,

17β-(N-neopentylcarbamoyl)-4-aza-5α-androst-1-en-3-one,

17β-(N-2-adamantylcarbamoyl)-4-aza-5α-androst-1-en-3-one,

17β-(N-1-adamantylcarbamoyl)-4-aza-5α-androst-1-en-3-one,

17β-(N-2-norbornylcarbamoyl)-4-aza-5α-androst-1-en-3-one,

17β-(N-1-norbornylcarbamoyl)-4-aza-5α-androst-1-en-3-one,

17β-(N-phenylcarbamoyl)-4-aza-4-methyl-5α-androst-1-en-3-one,

17β-(N-benzylcarbamoyl)-4-aza-4-methyl-5α-androst-1-en-3-one,

17β-(N-tert-amylcarbamoyl-4-aza-4-methyl-5α-androst-1-en-3-one,

17β-(N-tert-hexylcarbamoyl)-4-aza-4-methyl-5α-androst-1-en-3-one

17β-(N-tert-butylcarbamoyl)-4-aza-4-methyl-5α-androst-1-en-3-one

17β-(N-isobutylcarbamoyl)-4-aza-4-methyl-5α-androst-1-en-3-one,

17β-(N-tert-octylcarbamoyl)-4-aza-4-methyl-5α-androst-1-en-3-one

17β-(N-1,1,3,3-tetramethylbutylcarbamoyl)-4-aza-5α-androst-1-en-3-one,

17β-(N-octylcarbamoyl)-4-aza-4-methyl-5α-androst-1-en-3-one,

17β-(N-1,1-diethylbutylcarbamoyl)-4-aza-4-methyl-5α-androst-1-en-3-one,

17β-(N-neopentylcarbamoyl)-4-aza-4-methyl-5α-androst-1-en-3-one,

17β(N-1-adamantylcarbamoyl)-4-aza-5α-androstan-3-one;

17β(N-1-adamantylcarbamoyl)-4-methyl-4-aza-5α-androst-1-en-3-one;

17β(N-1-adamantylcarbamoyl)-4-methyl-4-aza-5α-androstan-3-one;

17β-(N-1-adamantylmethylcarbamoyl)-4-aza-5α-androst-1-en-3-one;

17β-(N-2-adamantylcarbamoyl)-4-aza-5α-androstan-3-one;

17β-(N-methyl-N-2-adamantylcarbamoyl)-4-methyl-4-aza-androstan-3-one;

17β-(N-2-adamantylcarbamoyl)-4-methyl-4-aza-5α-androstane-3-one;

17β-(N-2-adamantylcarbamoyl)-4-methyl-4-aza-5α-androst-1-en-3-one;

17β-(N-methyl-N-2-adamantyl)carbamoyl-4-methyl-4-aza-androst-1-en-3-one;

17β-(N-(3-methyl)-1-adamantyl-carbamoyl)-4-aza-4-methyl-5α-androst-an-3-one;

17β-(N-exo-2-norbornanylcarbamoyl)-4-aza-4-methyl-5α-androst-1-en-3-one;

17β-(N-exo-2-norbornanylcarbamoyl)-4-aza-5α-androst-1-en-3-one;17β-(N-2-adamantylcarbamoyl)-4-aza-5α-androst-en-3-one;

17β-(N-methyl-N-2-adamantylcarbamoyl)-4-aza-4-methyl-androstan-3-one;

17β-(N-2-adamantylcarbamoyl)-4-methyl-4-aza-5α-androstan-3-one; and

17β-(N-methyl-N-2-adamantyl)carbamoyl-4-methyl-4-aza-androst-1-en-3-one.

The corresponding compounds of those above wherein the 4-aza substituentis substituted in each of the above named compounds with a hydrogen,methyl or an ethyl radical, to form a different N-substituent, andwherein a double bond can be optionally present as indicated by thedotted line in position 1.

The alkyl, cycloalkyl, aralkyl, monocyclic aryl, 1-, 2-adamantyl or 1-,2-norbornanyl moieties can be substituted with one or more substituentsof the following: C₁ -C₄ linear/branched alkyl, including methyl, ethyl,isopropyl, n-butyl; nitro; oxo; C₇ -C₉ aralkyl, including benzyl; (CH₂)nCOOR where n is 0-2 and R is H or C₁ -C₄ linear/branched alkyl includingmethyl, ethyl; CH₂ OH; OH; OR where R is C₁ -C₄ linear/branched alkylincluding methyl, ethyl; halo, including fluoro, bromo, iodo; COOH;COOR, where R is linear/branched C₁ -C₄ alkyl; --CONH₂ ; CH₂ NH₂ ; CH₂NHCOR where R is C₁ -C₄ linear/branched alkyl including methyl, ethyl;phenyl; o, m, p-substituted phenyl including p-nitro, p-amino andp-sulfo; or cyano. The amino group of the adamantyl or norbornanylmoiety can also be substituted as R¹ with methyl and ethyl, as well ashydrogen.

Also included within the scope of this invention are pharmaceuticallyacceptable salts or esters, where a basic or acidic group is present onthe substituted alkyl, cycloalkyl, aralkyl, adamantyl or norbornanylmoiety. When an acidic substituent is present, i.e. --COOH, there can beformed the ammonium, sodium, potassium, calcium salt, and the like, foruse as the dosage form.

Where a basic group is present, i.e. amino, acidic salts, i.e.hydrochloride, hydrobromide, acetate, pamoate, and the like, can be usedas the dosage form.

Also, in the case of the --COOH group being present, pharmaceuticallyacceptable esters can be employed, e.g. acetate, maleate,pivaloyloxymethyl, and the like, and those esters known in the art formodifying solubility or hydrolysis characteristics for use as sustainedrelease or prodrug formulations.

Representative examples include for R² (where AD is adamantyl):

3,5,7-trinitro-1-AD; 4-oxo-1-AD; 1-benzyl-1-AD; 4,4-dimethyl-1-Ad;3,7-dimethyl-5-carboxymethyl-1-AD; 3-carboxymethyl-1-AD; 3-chloro-1-AD;1,3-dihydroxy-6,6-dimethyl-2-AD; 3-chloro-1-AD; 4-carbethoxy-2-AD;4-carboxy-2-AD; 3-isopropyl-1-AD; 3-n-butyl-1-AD; 3-propyl-1-AD;3-,5-diethyl-1-AD; 3-hydroxymethyl-1-AD; 2-carboxy-1-AD; 3-methyl-1-AD;5-hydroxy-2-AD; 2-hydroxy-1-AD; 1-aminomethyl-1-hydroxy-2-AD;2-oxo-1-AD; 2-phenyl-2-AD; 1-amino-methyl-2-AD; 1-carboxy-2-AD;1-aminocarbonyl-2-AD; 3-hydroxy-5,7-dimethyl-1-AD; 4-fluoro-1-AD;3-fluoro-1-AD; 4-hydroxy-2-AD; 3-phenyl-1-AD; 3-(p-aminophenyl)-1-AD;3-(p-nitrophenyl)-1-AD; 3-methyl-5-hydroxymethyl-1-AD;3,5-dimethyl-4-hydroxy-1-AD; 2-hydroxymethyl-2-AD;3-(p-sulfophenyl)-1-AD; 3-methyl-5-ethyl-1-AD; 2-carboxy-2-AD;3,5-7-trimethyl-1-AD; 4-iodo-2-AD; 4-bromo-2-AD; 4-chloro-2-AD;1-acetylaminomethyl-2-AD; 1-carboxymethyl-2-AD; 1-methyl-2-AD;1-aminocarboxylmethyl-2-AD; 1-aminocarboxyl-1-AD; 2-cyano-2-AD;3,5-dimethyl-7-ethyl-1-AD; 4-hydroxy-1-AD; 1-hydroxy-2-AD;5-carboxy-3-methyl-1-AD; 3,5-dimethyl-7-carboxy-1-AD; 3-carboxy-1-AD;3-hydroxy-1-AD; and the like.

Representative examples include for R² as substituted norbornanylmoieties are (where NB is norbornanyl):

2-NB; 1,7,7-trimethyl-4-phenyl-2-NB; 3-carboxy-2-NB;3-phenyl-2-carboxy-2-NB; 2-cyano-3-phenyl-2-NB;3-hydroxy-4,7,7-trimethyl-2-NB; 6-hydroxymethyl-2-NB; 5-cyano-2-NB;3-allyl-2-NB; 1-NB; 7,7-dimethyl-1-hydroxymethyl-2-NB;3-methoxy-4,7,7-trimethyl-2-NB; 3-aminocarbonyl-2-NB;3-ethoxycarbonyl-2-NB; 3,3-dimethyl-2-NB; 7-oxo-1-NB; 3-phenyl-2-NB;1-carboxy-methyl-7,7-dimethyl-2-NB; 1-ethyl-2-NB; 1-methyl-2-NB;2,2,3,3,5,5,6,6,7,7-decafluoro-1-NB; 3-hydroxy-2-NB; 3-chloro-2-NB;3-(p-methoxyphenyl)-2-NB; 2,2-dimethyl-3-methylene-7-NB; 3-oxo-2-NB;1-methoxy-2-NB; 7-NB; 3-isopropyl-2-NB; 2-bromo-1-NB; 3-chloro-1-NB; andthe like.

Procedures for preparing the compounds of Formula I useful in thisinvention, including the above, are well known in the art.

The novel compounds of formula I of the present invention can beprepared by a method starting with the known steroid ester (III) of theformula: ##STR3## 17β-(carbomethoxy)-4-aza-5-α-androstan-3-ones whichincludes the stages of optionally 1) dehydrogenating said startingmaterial to produce the corresponding compound containing a double-bondin the 1,2-position of the A-ring, 2) converting the 17-carbomethoxysubstituent into an N-substituted alkyl, cycloalkyl, aralkyl, monocylicacyl, or adamantylcarbamoyl substituent and, if desired, 3) alkylatingthe A-ring nitrogen to introduce a N-methyl or N-ethyl substituent intothe A ring 4-position. For the dehydrogenatin step, it is preferablethat the 4-aza nitrogen be unsubstituted. The alternate pathways canconsist of one or more discrete chemical steps and if desired can takeplace before step (1) or following step (1) or step (3).

In accordance with the process of the present invention (see flowsheet), the products of our invention are formed by optionally: (1)heating a 17β-alkoxycarbonyl-4-aza-5α-androstan-3-ones, compound III,(prepared in the literature as described in the reference U.S. Pat. No.4,377,584) with a dehydrogenating agent such as benzeneseleninicanhydride in a refluxing inert solvent, e.g. chlorobenzene, to form a17β-alkoxycarbonyl-4-aza-5α-androst-1-ene-3-one IV (alternately, thedichlorodicyanobenzoquinone process of Dolling, et al., JACS 1988, Vol.110, pp. 3318-3319, can be used); (2) the formed 5α-androst-1-en-3-onecompound from Step 1 can be reacted with, e.g. sodium hydride underanhydrous conditions in a neutral solvent such as dimethylformamide; (3)contacting the resulting reaction mixture with an alkyl (methyl orethyl) iodide to form the corresponding17-β-alkoxy-adamantyl-carbamoyl-4-alkyl-4-aza-5α-androst-1-en-3-one V;(4) subsequently hydrolyzing said17β-alkoxycarbonyl-4-alkyl-4-aza-5α-androst-1-en-3-one with a strongbase, such as aqueous methanolic potassium hydroxide at the refluxtemperature, followed by acidification and isolation of the resultingsteroidal acid to yield 17β-carboxy 4-alkyl-4-aza-5α-androst-1-en-3-oneVI; (5) said steroidal acid can be then converted to its corresponding2-pyridylthio ester by refluxing with triphenyl phosphine and2,2'-dipyridyl disulfide in an inert solvent such as toluene and theresulting product17β-(2-pyridylthiocarbonyl)-4-alkyl-4-aza-5α-androst-1-en-3-one VII canbe isolated by chromatography on e.g. silica gel; and (6) saidpyridylthio ester can be thenreacted with 1-adamantyl-, 2-adamantylamineor norbornanylamine in an inert solvent e.g. tetrahydrofuran, to formthe desired product17β-N-adamantylcarbamoyl-4-alkyl-4-aza-5α-androst-1-en-3-one VIII whichcan be isolated by chromatography e.g. on silica gel. When the previousreaction is carried out in the absence of first forming the double bondat position 1, the corresponding17β-(N-adamantylcarbamoyl)-4-alkyl-4-aza-5α-androstan-3-one (orN-norbornanyl carbamoyl compound) is prepared.

In accordance with an alternate process of our invention thecorrespondingN-unsubstituted-17β(N-adamantyl-carbamoyl)-4-aza-5α-androst-1-en-3-oneXIV is readily prepared from the 17β(alkoxycarbonyl)-4-aza-5α-androstone-3-one IV by repeating the aboveseries of reaction steps but omitting the alkylation Step 2 hereinabove, i.e. treatment of the 4-aza-5-α-androst-1-en-3-one with e.g.sodium amide followed by methyl or ethyl iodide via intermediates XIIand XIII.

In accordance with a further alternate process of preparing thecompounds of our invention having only hydrogen as the sole substituenton the ring A--nitrogen, the double bond in the A ring is introduced asthe last step of the process. Thus, a 17β-alkoxycarbonyl4-aza-5α-androstan-3-one III is hydrolyzed to the correspondingsteroidal acid IX 17β-carboxy-4-aza-5α-androstan-3-one which in turn isconverted to the corresponding pyridylthio ester, 17β(2-pyridylthiocarbonyl)-4-aza-5α-androstan-3-one, X followed bytreatment of the ester with an amine of formula R² -NH₂ wherein R² is asdefined hereinabove as 1- or 2-adamantyl or 1-, 2-, or 7-norbornanyl toform a 17β (N-adamantyl-carbamoyl)-4-aza-5α-androstone-3-one XI which isdehydrogenated as previously described to produce compound XIV,17β-(N-adamantyl-carbamoyl)-4-aza-androst-1-en-3-one or correspondingnorbornanyl derivative.

In another alternate method of introducing the17β-(N-adamantyl-carbamoyl)substituent into a 17β-carboxy androstanecompound of formula VI, XII or IX, each is treated in a manner similarto the procedure described in Steroids, Vol. 35 #3, March 1980, p. 1-7with dicyclohexylcarbodiimide and 1-hydroxybenzo-triazole to form the17β-(1-benzotriazoloxycarbonyl)-4-aza-5α-androst-1-en-3-one, VII, XIIIor compound X, wherein the substituent X is benzotriazoloxy group.

The 16-methyl derivative wherein R'" is methyl are prepared from known16-methyl-17-acyl-4-methyl-4-aza-5α-androstan-3-ones, e.g.4,16β-dimethyl-17β-acetyl-4-aza-5α-androstan-3-one by knowndehydrogenation procedures for 4-methyl-4-aza compounds to produce thecorresponding 4,16β-dimethyl-17β-acetyl-4-aza-5α-androst-1-en-3-one.

The above reactions are schematically represented in the followingflowsheet. ##STR4##

X is 2-pyridylthio or 1-benzotriazoloxy.

R² is 1- or 2-adamantyl or norbornanyl.

Also a preferred 4-azasteroid is a 17β-acyl-4-aza-5α-androst-1-ene-3-onecompound of the formula: ##STR5## wherein the dotted line represents adouble bond when present; R is selected from hydrogen, methyl and ethyl;

R² is (a) a monovalent radical selected from straight or branched chainalkyl, or cycloalkyl, of from 1-12 carbons, which can be substituted byone or more of C₁ -C₂ alkyl or halo;

(b) an aralkyl radical selected from benzyl or phenethyl;

(c) a polycyclic aromatic radical which can be substituted with one ormore of: --OH, protected --OH, --OC₁ -C₄ alkyl, C₁ -C₄ alkyl, halo ornitro;

(d) a monocyclic aromatic radical which can be substituted with one ormore of:

(1) --OH, --OC₁ -C₄ alkyl, C₁ -C₄ alkyl, --(CH₂)_(m) OH, --(CH₂)_(n),COOH, including protected hydroxy, where m is 1-4, n is 1-3, providingC₁ -C₄ alkyl is only present when one of the above oxygen-containingradicals is present;

(2) --SH, --SC₁ -C₄ alkyl, --SOC₁ -C₄ alkyl, --SO₂ C₁ -C₄ alkyl, --SO₂N(C₁ -C₄ -alkyl)₂, C₁ -C₄ alkyl --(CH₂)_(m) SH, --S--(CH₂)_(n) --O--COCH₃, where m is 1-4 n is 1-3, providing C₁ -C₄ alkyl is only presentwhen one of the above sulfur containing radicals is present;

(3) N(R³)₂, which can be protected, where R³ is independently H or C₁-C₄ alkyl, where the monoaryl ring can also be further substituted withC₁ -C₄ alkyl; and

(4) heterocyclic radical selected from 2- or 4-pyridyl, 2-pyrrolyl,2-furyl or thiophenyl;

and R', R" and R'" are each selected from hydrogen and methyl, andpharmaceutically acceptable salts thereof.

A preferred embodiment of the compounds of our invention process is:

the compound of above Structure IA,

wherein the dotted line is a double bond,

R is hydrogen or methyl, and

R² is branched chain alkyl, or cycloalkyl of from 4-10 carbons, and R"and R'" are hydrogen.

Another embodiment of the invention is the compounds of above StructureI where R² is phenyl, or phenyl substituted by substituents describedabove, including where

R² is phenyl, 2-, 3-, or 4-tolyl, xylyl, 2-bromophenyl, 2-chlorophenyl,2,6-dichlorophenyl, 2,6-dibromophenyl, aminophenyl, N-alkylaminophenyl,N-N-dialkylaminophenyl, 4-biphenyl, 3-biphenyl, naphthyl, anthracyl,phenanthryl, thiophenyl, methylthiophenyl, methylsulfinyl, phenyl,methylsulfophenyl, aminosulfophenyl, thioethylphenyl,acetoxymethylthiophenyl, 17β-(4-hydroxyphenyl), 17β-(3-hydroxyphenyl),17β-(3,4-dihydroxyphenyl), or 17β-(3,5-dimethyl-4-hydroxyphenyl).

Representative compounds of the invention are:

17β-(phenylcarbonyl)-4-aza-4-methyl-5α-androst-1-ene-3-one;

17β-(2-tolylcarbonyl)-4-aza-4-methyl-5α-androst-1-ene-3-one;

17β-(3-tolylcarbonyl)-4-aza-4-methyl-5α-androst-1-ene-3-one;

17β-(4-tolylcarbonyl)-4-aza-4-methyl-5α-androst-1-ene-3-one;

17β-(2-bromophenylcarbonyl)-4-aza-4-methyl-5α-androst-1-ene-3-one;

17β-(2-chlorophenylcarbonyl)-4-aza-4-methyl-5α-androst-1-ene-3-one;

17β-(2,6-dichlorophenylcarbonyl)-4-aza-4-methyl-5α-androst-1-ene-3-one;

17β-(2,6-dibromophenylcarbonyl)-4-aza-4-methyl-5α-androst-1-ene-3-one;

17β-(xylylcarbonyl)-4-aza-4-methyl-5α-androst-1-ene-3-one;

17β-(t-butylcarbonyl)-4-aza-5α-androst-1-ene-3-one;

17β-(isobutylcarbonyl)-4-aza-5α-androst-1-ene-3-one;

17β-(isooctylcarbonyl)-4-aza-5α-androst-1-ene-3-one;

17β-(n-octylcarbonyl)-4-aza-5α-androst-1-ene-3-one;

17β-(1,1-diethylbutylcarbonyl)-4-aza-5α-androst-1-ene-3-one;

17β-(neopentylcarbonyl)-4-aza-5α-androst-1-ene-3-one;

17β-(tert-amylcarbonyl)-4-aza-4-5α-androst-1-ene-3-one;

17β-(tert-hexylcarbonyl)-4-aza-4-5α-androst-1-ene-3-one;

17β-(cyclohexylcarbonyl)-4-aza-5α-androst-1-ene-3-one;

17β-(cyclopentylcarbonyl)-4-aza-5α-androst-1-ene-3-one;

17β-(benzylcarbonyl)-4-aza-5α-androst-1-ene-3-one;

17β-(2-pyridylcarbonyl)-4-aza-5α-androst-1-ene-3-one;

17β-(4-pyridylcarbonyl)-4-aza-5α-androst-1-ene-3-one;

17β-(2-pyrrolylcarbonyl)-4-aza-5α-androst-1-ene-3-one;

17β-(2-furylcarbonyl)-4-aza-5α-androst-1-ene-3-one;

17β-(2-thiophenylcarbonyl)-4-aza-5α-androst-1-ene-3-one;

17β-(2-adamantylcarbonyl)-4-aza-5α-androst-1-ene-3-one;

17β-(3-(phenylcarbonyl)-4-aza-5α-androst-1-ene-3-one;

17β-(2-tolylcarbonyl)-4-aza-5α-androst-1-ene-3-one;

17β-(3-tolylcarbonyl)-4-aza-5α-androst-1-ene-3-one;

17β-(4-tolylcarbonyl)-4-aza-5α-androst-1-ene-3-one;

17β-(2-bromophenylcarbonyl)-4-aza-5α-androst-1-ene-3-one;

17β-(2-chlorophenylcarbonyl)-4-aza-5α-androst-1-ene-3-one;

17β-(2,6-dichlorophenylcarbonyl)-4-aza-5α-androst-1-ene-3-one;

17β-(2,6-dibromophenylcarbonyl)-4-aza-5α-androst-1-ene-3-one;

17β-(xylylcarbonyl)-4-aza-5α-androst-1-ene-3-one;

17β-(phenylethyl)carbonyl-4-aza-5α-androst-1-ene-3-one;

17β-(4-dimethylaminophenylcarbonyl)-4-aza-5α-androst-1-en-3-one;

17β-(3-dimethylaminophenylcarbonyl)-4-aza-5α-androst-1-en-3-one.

17β-(3,4-diethylaminophenylcarbonyl)-4-aza-androst-1-en-3-one.

17β-(3,5-dimethyl-4-diethylaminophenylcarbonyl)-4-aza-5α-androst-1-en-3-one;

17β-(4-N-methylaminomethylphenylcarbonyl)-4-aza-5α-androst-1-en-3-one;or

17β-(2-N-ethylamino-4-ethylphenylcarbonyl)-4-aza-5α-androst-1-en-3-one.

17β-(4-phenylbenzoyl)-4-aza-5α-androst-1-en-3-one;

17β-(3-phenylbenzoyl)-4-aza-5α-androst-1-en-3-one;

17β-(4-biphenyl)-4-aza-5α-androst-1-en-3-one;

17β-(3-biphenyl)-4-aza-5α-androst-1-en-3-one;

17β-(1-naphthyl)-4-aza-5α-androst-1-en-3-one;

17β-(2-naphthyl)-4-aza-5α-androst-1-en-3-one;

17β-(1-phenanthryl)-4-aza-5α-androst-1-en-3-one;

17β-(2-phenanthryl)-4-aza-5α-androst-1-en-3-one;

17β-(1-biphenyl)-4-aza-5α-androst-1-en-3-one;

17β-(9-anthracyl)-4-aza-5α-androst-1-en-3-one;

17β-(4-thiophenylcarbonyl)-4-aza-5α-androst-1-en-3-one;

17β-(3-thiophenylcarbonyl)-4-aza-5α-androst-1-en-3-one;

17β-(4-methylthiophenylcarbonyl )-4-aza-5α-androst-1-en-3-one;

17β-(4-methylsulfinylphenylcarbonyl)-4-aza-5α-androst-1-en-3-one;

17β-(4-methylsulfophenylcarbonyl)-4-aza-5α-androst-1-en-3-one;

17β-(3-methylsulfinylphenylcarbonyl)-4-aza-5α-androst-1-en-3-one;

17β-(4-N,N-dimethylaminosulfophenylcarbonyl)-4-aza-5α-androst-1-en-3-one;

17β-(2-ethyl-4-methylthiophenylcarbonyl)-4-aza-5α-androst-1-en-3-one;

17β-(4-thioethylphenylcarbonyl)-4-aza-4-methyl-5α-androst-1-en-3-one;

17β-(4-acetoxymethylthiophenylcarbonyl)-4-aza-4-methyl5α-androst-1-en-3-one;

17β-(2-methyl-4-methylthiophenylcarbonyl)-4-aza-4-methyl-5α-androst-1-en-3-one;

17β-(2-methyl-4-methylsulfinylphenylcarbonyl)-4-aza-4-methyl-5α-androst-1-en-3-one;

17β-(2-isopropyl-4-methylsulfophenylcarbonyl)-4-aza-4-methyl-5α-androst-1-en-3-one;

17β-(4-methylthiophenylcarbonyl)-4-aza-4-methyl-5α-androstan-3-one;

17β-(4-methylsulfinylphenylcarbonyl)-4-aza-4-methyl-5α-androstan-3-one;

17β-(4-methylsulfophenylcatbonyl)-4-aza-4-methyl-5α-androstan-3-one;

17β-(4-hydroxyphenyl)-4-aza-5α-androst-1-en-3-one;

17β-(3-hydroxyphenyl)-4-aza-5α-androst-1-en-3-one;

17β-(3,4-dihydroxyphenyl)-4-aza-5α-androst-1-en-3-one;

17β-(3,5-dimethyl-4-hydroxyphenyl)-4-aza-5α-androst-1-en-3-one;

17β-(4-hydroxymethylphenyl)-4-aza-5α-androst-1-en-3-one;

17β-(2-hydroxyethylphenylcarbonyl)-4-aza-5α-androst-1-en-3-one;

17β-(4-methoxyphenyl)-4-aza-5α-androst-1-en-3-one;

17β-(4-carboxymethylphenyl)-4-aza-5α-androst-1-en-3-one;

17β-(4-hydroxyphenyl)-4-aza-4-methyl-5α-androst-1-en-3-one;

17β-(3-hydroxyphenyl)-4-aza-4-methyl-5α-androst-1-en-3-one;

17β-(3,4-dihydroxyphenyl)-4-aza-4-methyl-5α-androst-1-en-3-one;

17β-(3,5-dimethyl-4-hydroxyphenyl)-4-aza-4-methyl-5α-androst-1-en-3-one;

17β-(4-hydroxymethylphenyl)-4-aza-4-methyl-5α-androst-1-en-3-one;

17β-(2-hydroxyethylphenylcarbonyl)-4-aza-4-methyl-5α-androst-1-en-3-one;

17β-(4-methoxyphenyl)-4-aza-4-methyl-5α-androst-1-en-3-one;

17β-(4-carboxymethylphenyl)-4-aza-4-methyl-5α-androst-1-en-3-one; and

17β-(4-carboxyphenyl)-4-aza-5α-androst-1-en-3-one, and the correspondingcompounds wherein the 4-hydrogen substituent is replaced in each of theabove named compounds by a methyl or an ethyl radical.

The compounds of formula IA of the present invention are prepared by amethod starting with the known steroid ester of the formula: ##STR6##named 17β-(carbomethoxy)-4-aza-5α-androstan-3-one, which includes thestages of (1) dehydrogenating said starting material to produce thecorresponding compound containing a double bond in the 1,2-position ofthe A-ring, (2) converting the 17-carbomethoxy substituent into a17β-acyl substituent and, if desired (3) alkylating the A-ring nitrogento introduce 4-methyl or 4-ethyl substituents into the A-ring. For thedehydeogenation step, it is preferable that the 4-aza nitrogen beunsubstituted, The dehydrogenation step can be carried out, e.g.according to the procedure of Dolling, et al. involvingdichlorodicyanobenzoquinone, JACS (1988) Vol. 110, pp. 3318-3319. Stage(2) may consist of one or more chemical steps and if desired may takeplace before stage (1) or following stage (1) or stage (3).

In accordance with the process of the present invention, the products ofour invention are formed by (1) heating a17β-alkoxycarbonyl-4-aza-5α-androstan-3-one compound III with adehydrogenating agent such as benzeneseleninic anhydride in refluxingchlorobenzene to form a 17β-alkoxycarbonyl-4-aza-5α-androst-1-en-3-one(IV), (2) the formed 5α-androst-1-en-3-one compound from step (1) isreacted with sodium hydride and under anhydrous conditions in a neutralsolvent such as dimethylformamide, (2) contacting the resulting reactionmixture with an alkyl (methyl or ethyl) iodide to form the corresponding17β-alkoxycarbonyl-4-alkyl-4-aza-5α-androst-1-en-3-one (V), (3)subsequently hydrolyzing said17β-alkoxycarbonyl-4-alkyl-4-aza-5α-androst-1-en-3-one with a strongbase such as aqueous methanolic potassium hydroxide at the refluxtemperature, followed by acidification and isolation of the resultingsteroidal acid, 17β-carboxy-4-alkyl-4-aza-5α-androst-1-en-3-one (VI),(4) said steroidal acid is then converted to its corresponding2-thiopyridyl ester by refluxing with triphenyl phosphine and2,2'-dipyridyl disulfide in an inert solvent and the product17β-(2-pyridylthiocarbonyl)-4-alkyl-4-aza-5α-androst-1-en-3-one (VII) isisolated by chromatography on silica, (5) said pyridylthio ester is thenreacted with an R² -Li or an R² MgX (X=Cl, Br) compound, such assec-butylmagnesium chloride in tetrahydrofuran, to form the desiredproduct, e.g.,17β-(sec-butylcarbonyl)-4-alkyl-4-aza-5α-androst-1-en-3-one (VIII) whichis isolated by chromatography on silica gel. When the previous reactionis carried out using an R² MgX or, an R² -Li compound in place ofsec-butylmagnesium chloride, the corresponding17β-(acyl)-4-alkyl-4-aza-5α-androst-1-en-3-one is prepared wherein acylis R² carbonyl.

In accordance with the process of our invention, the corresponding17β-acyl-4-aza-5α-androst-1-en-3-one XV is readily prepared from the17β(alkoxycarbonyl)-4-aza-5α-androsten-3-one (IV) by repeating the aboveseries of reaction steps but omitting step 2 hereinabove, i.e.,treatment of the 4-aza-5α-androst-1-en-3-one with sodium amide followedby methyl or ethyl iodide.

In accordance with a further alternate process of preparing thecompounds of our invention, having only hydrogen as the sole substituenton the ring A-nitrogen, the 1,2-double bond in the A-ring is introducedas the last step of the process. Thus, a17β-alkoxycarbonyl-4-aza-5α-androstan-3-one (III) is hydrolyzed to thecorresponding steroidal acid, 17β-carboxy-4-aza-5α-androstan-3-one, (IX)which, in turn, is converted to the corresponding thiopyridyl ester,17β-(2-pyridylthiocarbonyl)-4-aza-5α-androstan-1-one (X) followed bytreatment of the ester with an R² MgX or R² Li compound wherein R² is asdefined hereinabove to form a 17β-(acyl)-4-aza-5α-androstan-3-one (XI)which is dehydrogenated as previously described to produce compound XIV,17β-(acyl)-4-aza-5α-androst-1-en-3-one.

In an additional alternative process for making the compounds of formulaI when the starting material is an ester, particularly methyl ester asshown in formula III-V in the schematic, reaction with a Grignardreagent R² MgX, gives the ketone, 17β-R² CO--, corresponding to the R²moiety associated with the Grignard reagent.

The 16-methyl derivative wherein R'" is methyl are prepared from known16-methyl-17β-acyl-4-methyl-4-aza-5α-androstan-3-ones, e.g.4,16β-dimethyl-17β-acetyl-4-aza-5β-androstan-3-one by knowndehydrogenation procedures for 4-methyl-4-aza compounds to produce thecorresponding 4,16β-dimethyl-17β-acetyl-4-aza-5α-androst-1-en-3-one.

The above reactions are schematically represented in the followingstructural outline: ##STR7## wherein X is a 2-pyridylthio substituentand R² is defined as hereinabove.

In the above described reaction Scheme, where R² is p-hydroxybiphenyl,this can be derived by starting with an appropriatebromobiphenylylphenol, e.g. p-bromobiphenylphenol, protecting thephenolic --OH with a conventional blocking group, e.g. trioganosilyl,i.e. t-butyldimethylsilyl, carrying out the Grignard reaction and thendeblocking the silyl group by the use of, e.g. refluxing aqueoustetrabutylammonium fluoride.

Other halo substituted benzenes to form the appropriate Grignard reagentuseful in the instant invention will be obvious to one skilled in theart from this disclosure.

By the term "protected hydroxy" as used herein, is meant the alcoholicor carboxylic --OH groups which can be protected by conventionalblocking groups in the art as described in "Protective Groups In OrganicSynthesis" by Theodora W. Greene, Wiley-Interscience, 1981, New York.Preferred are the triorganosilyl groups, e.g. t-butyldimethylsilyl,phenyldimethylsilyl, diphenylmethylsilyl, and the like.

By the term "C₁ -C₄ alkyl" is used herein, is meant linear or branchedalkyl, including methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl,sec-butyl and t-butyl.

When this reaction scheme is carried out using an R² MgX or R² -Licompound containing an thiophenyl substituted R², e.g.p-methylthiophenyl magnesium chloride, the corresponding17β-(substituted thio-benzoyl)-4-alkyl aza-5α-androst-1-en-3-one isprepared wherein phenyl is R².

The Grignard reagent, R² MgX, for all the species included within thescope of this invention, are available or can readily be made by oneskilled in the art. For example, where R² is C₁ -C₄ alkyl thiophenyl,can be formed from the appropriate C₁ -C₄ alkyl thiobromobenzene, e.g.p-methylthiobromobenzene.

The formed C₁ -C₄ alkyl thiobenzene can be used to further prepare C₁-C₄ alkyl sulfoxides by oxidation with e.g. m-chloroperbenzoic acid. Theresulting sulfoxide can be further oxidized by the use of them-chloroperbenzoic acid reaction to proceed for a longer period of timeto form the C₁ -C₄ alkyl sulfone.

Further, the sulfoxide can be used in the Pummerer rearrangement to formthe corresponding thiol.

The --SO₂ N(C₁ -C₄ alkyl)₂ substituted phenyl (R²) is formed from theappropriate bromobenzene, e.g. p-N,N-dimethylaminosulfobromobenzenewhich is used directly in the Grignard reaction to form the finalproduct.

The thioalkyl groups on the phenyl ring, i.e. --(CH₂)_(m) SH, where m is1-4, are readily formed via a four step procedure from an alkoxy alkylphenyl bromide, Br--C₆ H₄ --(CH₂)_(m) OCH₃. Direct addition of theGrignard reagent prepared from above-bromoalkyl phenyl derivative to thethiopyridyl ester results in the keto derivative, i.e.17β(4-methoxyalkyl-benzoyl)-4-aza-5α-androst-1-ene-3-one. This can bereadily converted into thio analogue via BBr₃ at -70° C. to form thehydroxyalkyl derivative, followed by displacement by halogen, e.g. bromoand then converting the halogenated compound through NaSH displacementto give the final mercapto compound. Where in the Reaction Scheme saidpyridylthio ester is reacted with an aminophenyl containing R² -Li or anR² MgX (X=Cl, Br) compound, such as p-dimethylaminophenyl magnesiumchloride, this is carried out in tetrahydrofuran to form the desiredproduct17β-(p-dimethylaminophenyl-carbonyl)-4-alkyl-4-aza-5α-androst-1-en-3-one(VIII) which is isolated by chromatography on silica gel.

The Grignard reagent, R² MgX, for all of the aminophenyl speciesincluded within the scope of this invention, are available and can bemade readily by one skilled in the art.

Where in the process said Grignard reagent contains a phenolic type R²moiety, then said pyridylthio ester is then reacted with an R² -Li or anR² MgX (X=Cl, Br) Grignard reagent, such as p-methoxyphenyl-magnesiumchloride in tetrahydrofuran to form the desired product, e.g.17β-(p-methoxyphenylcarbonyl)-4-alkyl-4-aza-5α-androst-1-en-3-one (VIII)which is isolated by chromatography on silica gel. When this reaction iscarried out using another R² MgX or, an R² -Li compound in place ofp-methoxyphenylmagnesium chloride, the corresponding 17β-(substitutedbenzoyl)-4-alkyl-4-aza-5α-androst-1-en-3-one is prepared wherein phenylis R².

The Grignard reagent, R² MgX, for all of the species included within thescope of this invention, are available and can be made readily by oneskilled in the art.

For example, where R² is hydroxyphenyl, this can be derived by startingwith an appropriate bromophenol, e.g. p-bromophenol, protecting thephenolic --OH with a conventional blocking group, e.g. trioganosilyl,i.e. t-butyldimethylsilyl, carrying out the Grignard reaction and thendeblocking the silyl group by the use of, e.g. refluxing aqueoustetrabutylammonium fluoride.

For R² being hydroxyethylphenyl, the same blocking procedure can beanalogously conducted starting with the appropriate hydroxyalkylbromophenol, e.g. p-hydroxymethylbromobenzene, orp-hydroxyethylbromobenzene.

Where R² is carboxyphenyl, this can be obtained by the chromic acidoxidation of the appropriate hydroxymethylbenzene, e.g.p-bromo-hydroxymethylbenzene, formed as described above.

Where R² is -O-C₁ -C₄ alkyl, the appropriate bromo-O-C₁ -C₄ alkylbenzene, e.g. p-methoxybromobenzene, is utilized for the Grignardreaction.

Other halo substituted benzenes to form the appropriate Grignard reagentuseful in the instant invention will be obvious to one skilled in theart from this disclosure.

By the term "protected hydroxy" as used herein, is meant the alcoholicor carboxylic --OH groups which can be protected by conventionalblocking groups in the art as described in "Protective Groups In OrganicSynthesis" by Theodora W. Greene, Wiley-Interscience, 1981, New York.Preferred are the triorganosilyl groups, e.g. t-butyldimethylsilyl,phenyldimethylsilyl, diphenylmethylsilyl, and the like.

Also within the scope of the present invention is the use of ketonereduction products of IA, in combination with flutamide for treatment ofprostatic carcinoma, being secondary alcohols of the formula: ##STR8##wherein R is selected from hydrogen, methyl and ethyl; R² is (a) amonovalent radical selected from straight or branched chain alkyl, orcycloalkyl, of from 1-12 carbons, which can be substituted by one ormore of C₁ -C₂ alkyl or halo;

(b) an aralkyl radical selected from benzyl or phenethyl;

(c) a polycyclic aromatic radical which can be substituted with one ormore of: --OH, protected --OH, --OC₁ -C₄ alkyl, C₁ -C₄ alkyl, halo ornitro;

(d) a monocyclic aromatic radical which can be substituted with one ormore of:

(1) --OH, --OC₁ -C₄ alkyl, C₁ -C₄ alkyl, --(CH₂)_(m) OH, --(CH₂)_(n)COOH, including protecting hydroxy, where m is 1-4, n is 1-3, providingC₁ -C₄ alkyl is only present when one of the above oxygen-containingradicals is present;

(2) --SH, --SC₁ -C₄ alkyl, --SOC₁ -C₄ alkyl, --SO₂ C₁ -C₄ alkyl, --SO₂N(C₁ -C₄ -alkyl)₂, C₁ -C₄ alkyl --(CH₂)_(m) SH, --S--(CH₂)_(n) --O--COCH₃, where m is 1-4 n is 1-3, providing C₁ -C₄ alkyl is only presentwhen one of the above sulfur containing radicals is present;

(3) N(R³)₂, which can be protected, where R³ is independently H or C₁-C₄ alkyl, where the monoaryl ring can also be further substituted withC₁ -C₄ alkyl; and

(4) heterocyclic radical selected from 2- or 4-pyridyl, 2-pyrrolyl,2-furyl or thiophenyl;

R', R" and R'" are hydrogen or methyl, wherein the dotted linerepresents a double bond which can be present, and pharmaceuticallyacceptable salts and esters thereof.

These compounds can be made by conventional sodium borohydride reductionof the carbonyl attached to R² without reducing the amide carbonyl inRing A or the 1,2-double bond, if present. If the R² phenyl contains acarbonyl function, it can be selectively blocked and then regeneratedafter the borohydride reduction by conventional methods.

The borohydride reduction can be carried out in, e.g. water or aqueousmethanol, at a temperature of room temperature to 50° C. and the productthen isolated and purified by conventional means. The compounds are alsoactive as 5-alpha reductase inhibitors in the treatment of patternedalopecia.

The compounds of the present invention, prepared in accordance with themethod described above, are, as already described, potent agents incombination with an antiandrogen, e.g. flutamide for the treatment ofprostatic cancer.

17β-substituted steroidal 5α-reductase inhibitors which are non-4-azasteroids are known in the art and include those developed by SmithKlineBeckmann as disclosed in U.S. Pat. No. 4,882,319 to Holt, et al.; U.S.Pat. No. 4,910,226 to Holt, et al; EPO Publn. 0 289 327 now U.S. Pat.No. 4,910,226; EPO Publn. 0 277 002 now U.S. Pat. No. 4,888,336; EPOPubln. 0 343 954; EPO Publn. 0 375 344 now U.S. Pat. No. 4,937,237; EPOPubln. 0 375 347; now U.S. Pat. No. 4,970,205; EPO Publn. 0 375 349; nowU.S. Pat. No. 5,026,882.

In the method the 17β-substituted non-aza steroids are of the formula:##STR9## in which: the A ring has up to 2 double bonds;

the B, C, and D rings have optimal double bonds where indicated by thebroken lines, provided that the A, B, and C rings do not have adjacentdouble bonds and the D ring does not have a C₁₆ -C₁₇ double bond when R₃represents two substituents or a divalent substituent;

Z is (CH₂)n and n is 0 or 2, provided that Z is (CH)n when adjacent to adouble bond;

X is H, Cl, F, Br, I, CF₃, or C₁₋₆ alkyl;

Y is H, CF₃, F, Cl, or CH₃, provided that Y is H when there is no C₅ -C₆double bond;

R¹ is H or C₁₋₈ alkyl;

R² is absent or present as H or CH₃, provided R² is absent when thecarbon to which it is attached is unsaturated; and

R³ is

(1) α-hydrogen, or α-hydroxyl, or α-acetoxy and/or

(a) ##STR10## where W is a bond or C₁₋₁₂ alkylidene, and R⁴ is (i)hydrogen,

(ii) hydroxyl,

(iii) C₁₋₈ alkyl,

(iv) hydroxylic C₁₋₈ alkyl,

(v) C₁₋₈ alkoxy,

(vi) NR⁵ R⁶, where R⁵ and R⁶ are each independently selected fromhydrogen, C₁₋₈ alkyl, C₃₋₆ cycloalkyl, phenyl; or R⁵ and R⁶ takentogether with the nitrogen to which they are attached represent a 5-6membered saturated ring,

(vii) OR⁷, where R⁷ is hydrogen, alkali metal, C₁₋₈ alkyl, benzyl, or

(b) --Alk--OR⁸, where Alk is C₁₋₂ alkylidene, and R⁸ is

(i) phenyl C₁₋₆ alklycarbonyl,

(ii) C₅₋₁₀ cycloalkylcarbonyl,

(iii) benzoyl,

(iv) C₁₋₈ alkoxycarbonyl,

(v) aminocarbonyl, or C₁₋₈ alkyl substituted aminocarbonyl,

(vi) hydrogen, or

(vii) C₁₋₈ alkyl,

(2) ═CH--W--CO--R⁴ or ═CH--W--OR⁸, where W is a bond of C₁₋₁₂ alkylideneand R⁴ and R⁸ have the same meaning as above and R8 also is hydrogen orC₁₋₂₀ alkylcarbonyl,

(3) ##STR11## where the dashed bond replaces the 17-α-hydrogen, (4)α-hydrogen and NHCOR⁹ where R⁹ is C₁₋₁₂ alkyl or NR⁵ R⁶ where R⁵ and R⁶have the same meaning as above,

(5) α-hydrogen and cyano,

(6) α-hydrogen and tetrazolyl, or

(7) keto;

or a pharmaceutically acceptable salt thereof; except compounds inwhich:

(i) the B ring has a C₅ -C₆ double bond, R¹ is CH₃, and R³ is keto,methoxycarbonyl, or acetyl; or

(ii) the A-nor ring has a C₃ -C₄ double bond and R³ is acetoxy oracetyl;

(iii) R¹ is CH₃ and R³ is acetoxy or acetyl; or

(iv) the A-nor ring has a C₃ -C₄ double bond and R¹ is methyl; or

(v) the B ring has a C₃ -C₄ double bond and R³ is β-hydroxy.

Representative compounds whose synthesis and properties are disclosed inthe above issued US patents include the following and pharmaceuticallyacceptable salts thereof:

4-methyl-4-aza-5α-8(14)-pregnen-3-one-(20R)-20-carboxylic acid;

(20R)-hydroxymethyl-4-methyl-4-aza-5α-8(14)-pregnen-3-one;

4-methyl-4-aza-5α-8(14)-androsten-3-one-17β-N,N-diisopropylcarboxamide;

17β-(N,N-diisopropylcarboxamide)-estr-1,3,5(10)-triene-3-phosphonicacid;

17β-(N-tert-butylcarboxamide)-estr-1,3,5(10)-triene-3-phosphonic acid;

17β-(N,N-diisopropylcarboxamide)-estr-1,3,5(10),16-tetraene-3-phosphonicacid;

17β-(N-tert-butylcarboxamide)-estr-1,3,5(10),16-tetraene-3-phosphonicacid;

17β-(N,N-diisopropylcarboxamide)-estr-1,3,5(10),6,8-pentaene-3-phosphonicacid;

17β-(N,N-diisopropylcarboxamide)-2-methyl-estr-1,3,5(10)triene-3-phosphonicacid;

17β-(N,N-diisopropylcarboxamide)-4-methyl-estr-1,3,5(10)-triene-3-phosphonicacid;

17β-(N-N-diisopropylcarboxamide)-estr-1,3,5(10),6-tetraene-3-phosphonicacid;

17β-(N-N-diisopropylcarboxamide)-2-chloro-estr-1,3,5(10)-triene-3-phosphonicacid;

17β-(N-N-diisopropylcarboxamide)-4-chloro-estr-1,3,5(10)-triene-3-phosphonicacid;

17β-(N-butylcarboxamide)-estr-1,3,5(10)-triene-3carboxylic acid;

17β-(N-butylcarboxamide)-estr-1,3,5(10)16-tetraene-3-carboxylic acid;

17β-(N,N-diisopropylcarboxamide)-estr-1,3,5(10)-triene-3-phosphinicacid;

17β-(N-tert-butylcarboxamide)-estr-1,3,5(10)-triene-3-phosphinic acid;

17β-(N,N-diisoprPpylcarboxamide)-2-methyl-estr-1,3,5(10)-triene-3-phosphinicacid;

17β-(N,N-diisopropylcarboxamide)-4-methyl-estr-1,3,5(10)-triene-3-phosphinicacid;

17β-(N,N-diisopropylcarboxamide)-2-chloro-estr-1,3,5(10)-triene-3-phosphinicacid;

17β-(N,N-diisopropylcarboxamide)-4-chloro-estr-1,3,5(10)-triene-3-phosphinicacid;

17β-(N,N-diisopropylcarboxamide)-1,3,5(10),16-tetraene-3-phosphinicacid;

17β-(N-tert-butylcarboxamide)-estr-1,3,5(10),16-tetraene-3-phosphinicacid;

17β-(N,N-diisopropylcarboxamide)-estr-1,3,5(10),6,8-pentaene-3-phosphinicacid;

17β-(N,N-diisopropylcarboxamide)-estr-1,3,5(10),6-tetraene-3-phosphinicacid;

17β-(N,N-diisopropylcarboxamide)-estr-1,3,5(10)-triene-3-phosphonicacid;

17β-(N-tert-butylcarboxamide)-estr-1,3,5(10)-triene-3-phosphonic acid;

17β-(N,N-diisopropylcarboxamide)-estr-1,3,5(10),16-tetraene-3-phosphonicacid;

17β-(N-tert-butylcarboxamide)-estr-1,3,5(10),16-tetraene-3-phosphonicacid;

17β-(N,N-diisopropylcarboxamide)-estr-1,3,5(10),6,8-pentaene-3-phosphonicacid;

17β-(N,N-diisopropylcarboxamide)-2-methyl-estr-1,3,5(10)-triene-3-phosphonicacid;

17β-(N,N-diisopropylcarboxamide)-4-methyl-estr-1,3,5(10)-triene-3-phosphonicacid;

17β-(N,N-diisopropylcarboxamide)-estr-1,3,5(10),6-tetraene-3-phosphonicacid;

17β-(N,N-diisopropylcarboxamide)-2-chloro-estr-1,3,5(10)-triene-3-phosphonicacid;

17β-(N,N-diisopropylcarboxamide)-4-chloro-estr-1,3,5(10)-triene-3-phosphonicacid;

17β-(N,N-diisopropylcarboxamide)-estr-1,3,5(10)-triene-3-sulfonic acid;

17β-(N-tert-butylcarboxamide)-estr-1,3,5(10)-triene-3-sulfonic acid;

17β-(N,N-diisopropylcarboxamide)-estr-1,3,5(10),16-tetraene-3-sulfonicacid;

17β-(N-tert-butylcarboxamide)-estr-1,3,5(10),16-tetraene-3-sulfonicacid;

17β-(N,N-diisopropylcarboxamide)-estr-1,3,5(10),6,8-pentaene-3-sulfonicacid;

17β-(N,N-diisopropylcarboxamide)-2-methyl-estr-1,3,5(10)-triene-3-sulfonicacid;

17β-(N,N-diisopropylcarboxamide)-4-methyl-estr-1,3,5(10)-triene-3-sulfonicacid;

17β-(N,N-diisopropylcarboxamide)-2-chloro-estr-1,3,5(10)-triene-3-sulfonicacid;

17β-(N,N-diisopropylcarboxamide)-4-chloro-estr-1,3,5(10)-triene-3-sulfonicacid;

17β-(N,N-diisopropylcarboxamide)-androst-3,5-diene-3-phosphinic acid;

17β-(N-t-butylcarboxamide)-androst-3,5-diene-3-phosphinic acid;

17β-(N,N-diisopropylcarboxamide)-5α-androst-3-ene-3-phosphinic acid;

17β-(N,N-diisopropylcarboxamide)-5α-androst-2-ene-3-phosphinic acid;

17β-(N,N-diisopropylcarboxamide-androst-2,4-diene-3-phosphinic acid;methyl(17β-N,N-diisopropylcarboxamide)-androst-3,5-diene-3-phosphinicacid;

20α-(hydroxymethyl)-5α-pregn-3-ene-3-phosphinic acid;

17β-(N,N-diisopropylcarboxamide)-4-fluoro-5α-androst-3-ene-3-phosphinicacid;

20α-(hydroxymethyl)-4-fluoro-5α-pregn-3-ene-3-phosphinic acid;

20α-(hydroxymethyl)-A-nor-5α-pregn-1-ene-2-phosphinic acid;

17β-(N,N-diisopropylcarboxamide)-5α-androst-1,3-diene-3-phosphinic acid;

17β-(N,N-diisopropylcarboxamide)-5α-androstane-3β-phosphinic acid;

17β-(N,N-diisopropylcarboxamide)-estr-3,5(10)-diene-3-phosphinic acid;

17β-(N,N-Diisopropylcarboxamide)-estr-3,5-diene-3-phosphinic acid;

17β-(N,N-Diisopropylcarboxamide)-androst-3,5-11-triene-3-phosphinicacid.

20α-(hydroxymethyl)-5α-pregn-3-ene-3-carboxylic acid;

N,N-diisopropyl-5α-androst-3-ene-17β-carboxamide-3 carboxylic acid;

N,N-diisopropyl-androst-3,5-diene 17β-carboxamide-3-carboxylic acid;

17β-(N,N-diisopropylcarboxamide)-4-fluoro-5α-androst-3-ene-3-carboxylicacid;

20α-(hydroxymethyl)-4-fluoro-5α-pregn-3-ene-3-carboxylic acid;

20α-(hydroxymethyl)-A-nor-5α-pregn-1-ene-2-carboxylic acid;

17β-N,N-diisopropylcarboxamide-5α-androst-1,3-diene-3-carboxylic acid;

N-t-Butyl Androst-3,5-diene-17β-carboxamide-3-carboxylic acid;

N,N-Diisopropyl-5α-Androst-2-ene-17β-carboxamide-3-carboxylic acid;

N,N-Diisopropyl Androst-2,4,-diene-17β-carboxamide-3-carboxylic acid;

N,N-Diisopropyl 5α-Androstane-17β-carboxamide carboxylic acid;

N,N-Diisopropyl Estr-3,5(10)-diene-17β-carboxamide-3-carboxylic acid;

N,N,-Diisopropyl Estr-3,5-diene-17β-carboxamide-3-carboxylic acid;

20α(hydroxymethyl)-5α-pregn-3-ene-carboxylic acid

N,N-diisopropyl-5α-androst-3-ene-17β-carboxamide-3-carboxylic acid;

N,N-diisopropyl-androst-3,5-diene-17β-carboxamide-3-carboxylic acid;

17β-(N,N-diisopropylcarboxamide)-4-fluoro-5α-androst-3-ene-3-carboxylicacid;

17β-(N,N-Diisopropylcarboxamide)-androst-3,5,11-triene-3-carboxylicacid;

17β-(N,N-Diisopropylcarboxamide)-androst-3,5-diene-3-thiocarboxylicacid;

17β-(N-t-Butylcarboxamide)-androst-3,5,11-triene-3-carboxylic acid;

17β-(N-t-Butylcarboxamide)-androst-3,5-diene-3-thiocarboxylic acid,

N-t-butyl-androst-3,5-diene-17β-carboxamide-3-carboxylic acid,

N,N-diisopropyl-androst-3,5-diene-17β-carboxamide-3-carboxylic acid,

20α-(hydroxymethyl)-3-α-pregn-3-ene-3-carboxylic acid,

20α-(hydroxymethyl)-4-fluoro-5-α-pregn-3-ene-3-carboxylic acid,

3-carbomethoxy-N,N-diisopropyl-androst-3,5-diene-17β-carboxamide,

17β-N,N-diisopropylcarboxamide-5-α-androst-1,3-diene-3-carboxylic acid,

N,N-Diisopropyl 5-α-androst-2-ene-17β-carboxamide-3-carboxylic acid,

N,N-diisopropyl androst-2-4-diene-17β-carboxamide-3-carboxylic acid,

N,N-diisopropyl 5-α-androstane-17β-carboxamide-3β-carboxylic acid, and

N,N-diisopropyl estr-3,5(10)-diene-17β-carboxamide-3-carboxylic acid.

The benzoylaminophenoxy butanoic acid derivatives are of the formula:##STR12## wherein R' is hydrogen or alkyl of from 1 to 4 carbon atom(s);A is oxygen atom, sulfur atom or sulfinyl (SO) group; both R¹ 's aremethyl or chlorine, or the two R¹ 's and the carbon atoms of the benzenering to which the two R¹ 's are linked together are cyclopentane,cyclohexane or a benzene ring; and

R² represents a group of formula: ##STR13## wherein B is oxygen, sulfuror a group of formula: NR¹¹ wherein R¹¹ is hydrogen or alkyl of from 1to 4 carbon atom(s),

R³, R⁴, R⁵, R⁶, R⁷, and R⁸ are, independently, hydrogen, alkyl of from 1to 4 carbon atom(s), halogen, trifluoromethyl or cyclobutylmethyl,

m is 0 or 1,

n is an integer of from 1 to 5, and

R⁹ is a hydrogen, alkyl of from 1 to 5 carbon atom(s) or a group offormula: ##STR14## wherein R¹², R¹³, R¹⁴, and R¹⁵ are, independently,hydrogen, alkyl of from 1 to 4 carbon atom(s), halogen, trifluoromethylor cyclobutylmethyl, and 1 is an integer of from 1 to 4, and

R¹⁰ is a group of formula: ##STR15## wherein R¹², R¹³, R¹⁴, and R¹⁵ are,independently, hydrogen, alkyl of from 1 to 4 carbon atom(s), halogen,trifluoromethyl or cyclobutylmethyl, and 1' is an integer of from 1 to4; or non-toxic salts thereof.

Representative examples of each of these two classes of compounds whosesynthesis and properties are disclosed in the above cited US issuedpatents include the following:

4-[2-(4-benzyloxy-2,3-dimethylbenzoylamino)phenoxy]butanoic acid;

4-[2-[4-(2-methylbenzyloxy)-2,3-dimethylbenzoylamino]butanoic acid;

4-[2-[4-(3-methylbenzyloxy)-2,3-dimethylbenzoylamino]phenoxy]butanoicacid;

4-[2-[(4-methylbenzyloxy)-2,3-dimethylbenzoylamino]phenoxy]butanoicacid;

4-[2-[4-(2,6-dimethylbenzyloxy)-2,3-dimethylbenzoyl-amino]phenoxy]butanoicacid;

4-[2-[4-(4-ethylbenzyloxy)-2,3-dimethylbenzoylamino]phenoxy]butanoicacid;

4-[2-[4-(4-propylbenzyloxy)-2,3-dimethylbenzoylamino]phenoxy]butanoicacid;

4-[2-[4-(4-isopropylbenzyloxy)-2,3-dimethylbenzoyl-amino]phenoxy]butanoicacid;

4-[2-[4-(4-isobutylbenzyloxy)-2,3-dimethylbenzoyl-amino]phenoxy]butanoicacid;

4-[2-[4-(4-chlorobenzyloxy)-2,3-dimethylbenzoylamino]phenoxy]butanoicacid;

4-[2-[4-(4-cyclobutylmethylbenzyloxy)-2,3-dimethylbenzoylamino]phenoxy]butanoicacid;

4-[2-[4-(2-phenylethoxy)-2,3-dimethylbenzoylamino]phenoxy]butanoic acid;

4-[2-[4-(3-phenylpropoxy)-2,3-dimethylbenzoylamino]phenoxy]butanoicacid;

4-[2-[4-(4-phenylbutoxy)-2,3-dimethylbenzoylamino]phenoxybutanoic acid;

4-[2-[4-(5-phenylpentyloxy)-2,3-dimethylbenzoylamino]phenoxy]butanoicacid;

4-[2-[4-(1-(4-isobutylphenyl)ethoxy)-2,3-dimethylbenzoylamino]phenoxy]butanoicacid;

4-[2-[4-(4-propylbenzyloxy)-2,3-dimethylbenzoylamino)phenylthio]butanoicacid;

4-[2-[1-(4-isobutylphenyl)ethoxy)-2,3-dimethylbenzoylamino]phenylthio]butanoicacid;

4-[2-[4-(4-propylbenzyloxy)-2,3-dimethylbenzoylamino]phenylsulfinyl)butanoicacid;

4-[2-[4-[N-(4-trifluoromethylphenylmethyl)amino)-2,3-dimethylbenzoylamino]phenoxy]butanoicacid;

4-[2-[4-(4-isobutylbenzyloxy)-5,6,7,8-tetrahydronaphthalene-1-carbonylamino)phenoxybutanoicacid;

4-[2-[4-(4-isobutylbenzyloxy)naphthalene-1-carbonylamino)phenoxy)butanoicacid;

4-[2-[8-(4-isobutylbenzyloxy)-5,6,7,8-tetrahydronaphthalene-1-carbonylamino)phenylthio]butanoicacid;

4-[2-[4-[bis(4-propylphenyl)methoxy]2,3-dimethylbenzoylamino)phenoxy]butanoicacid;

4-[2-(4-diphenylmethoxy)-2,3-dimethylbenzoylamino)phenoxy]butanoic acid;

4-[2-[4-[bis(4-propylphenyl)methylamino]-2,3-dimethylbenzoylamino]phenoxy]butanoicacid;

4-[2-[4-[bis-(4-propylphenyl)methylthio]-2,3-dimethylbenzoylamino]phenoxy]butanoicacid;

4-[2-[4-[N,N-bis(4-propylphenylmethyl)amino]-2,3-dimethylbenzoylamino]phenoxy]butanoicacid;

4-[2-[4-[N,N-bis(4-trifluoromethylphenylmethyl)amino]-2,3-dimethylbenzoylamino]phenoxy]butanoicacid;

4-[2-[4-N-methyl-N-(5,6,7,8-tetrahydronaphth-1-yl]aminomethyl]-2,3-dimethylbenzoylamino]phenoxy]-butanoicacid;

8-(p-pentylbenzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane;

8-(p-pentylbenzoyl)amino-2-(5-tetrazolyl)-6 chloro-1,4-benzodioxane;

8-(m-octylbenzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane;

8-(o-pentylbenzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane;

8-(p-butylbenzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane;

8-(p-hexylbenzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane;

8-(p-heptylbenzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane;

8-(p-octylbenzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane;

8-(p-nonylbenzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane;

8-(p-decylbenzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane;

8-(p-undecylbenzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane;

8-(p-dodecylbenzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane;

8-(p-pentyloxybenzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane;

8-(m-pentyloxybenzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane;

8-(o-pentyloxybenzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane;

8-(p-butyloxybenzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane;

8-(p-nonyloxybenzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane;

8-(p-propoxybenzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane;

8-(p-hexyloxybenzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane;

8-(p-heptyloxybenzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane;

8-(p-octyloxybenzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane;

8-(o-decyloxybenzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane;

8-(p-isopentyloxybenzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane;

8-(p-isohexyloxybenzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane;

8-[p-(1-methylbutoxy)benzoyl]amino-2-(5-tetrazolyl)-1,4-benzodioxane;

8-(N-methyl-N-(p-octynyloxy)benzoyl])amino-2-(5-tetrazolyl)-1,4-benzodioxane;

8-(p-oxtyloxybenzoyl)amino-1,4-benzodioxane-2-carboxylic acid and methylester thereof;

8-(p-isoheptyloxybenzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane;

8-(p-isooctyloxybenzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane;

8-[p-(3,7-dimethyloctyloxy)benzoyl]amino-2-(5-tetrazolyl)-1,4-benzodioxane;

8-(p-octyloxybenzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane;

8-(p-heptyloxybenzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane-7-carboxylicacid and methyl ester thereof, and the like.

Also included as a 5α-reductase inhibitor in this invention is acinnamoylamide of the following formula: ##STR16## wherein R² and R³each independently represents a hydrogen or methyl group with theproviso that

(i) when R² represents a methyl group, R³ represents hydrogen and (R¹)nrepresents a member selected from the group consisting of 3-group,4-pentyl group, 4-neopentyl group, 4-(2-ethylbutyl) group and4-(2-methylpentyl) group, or

(ii) when R² represents hydrogen, R³ represents a methyl group and (R¹)nrepresents a 3-pentyl group, or non-toxic salts thereof.

Representative compounds include:

4-[2-(4-butylthio-β-methylcinnamoylamino)phenoxy]butanoic acid

4-[2-(4-cyclobutylmethy)β-methylcinnamoylamino)phenoxy]butanoic acid

4-[2-(4-cyclohexylmethyl)β-methylcinnamoylamino)phenoxy]butanoic acid

4-[2-(4-{4-phenylbutyl)-β-methylcinnamoylamino)phenoxy]butanoic acid

4-[2-(4-phenoxy-β-methylcinnamoylamino)phenoxy]butanoic acid

4-[2-(3-pentyl-α-methylcinnamoylamino)phenoxy]butanoic acid

4-[2-(4-phenethyl-α-methylcinnamoylamino)phenoxy]butanoic acid

4-[2-(3-pentyl-β-methylcinnamoylamino)phenoxy]butanoic acid

4-[2-(4-neopentyl]-β-methylcinnamoylamino)phenoxy]butanoic acid

4-[2-{4-(2-ethylbutyl)-β-methylcinnamoylamino)phenoxy]butanoic acid,

4-[2-{4-(2-methylpentyl)-β-methylcinnamoylamino)phenoxy]butanoic acid,and

4-[2-(2-fluoro-4-pentylexy-β-methylcinnamoylamino)phenoxy]butanoic acid.

Also included in this invention are fused benz(thio) amides of theformula: ##STR17## wherein A represents a single bond or a group ofmethylene, ethylene, trimethylene, tetramethylene, vinylene,propenylene, butenylene, butadienylene or ethynylene group optionallybeing substituted by one, two or three of straight or branched alkylgroup(s) of from 1 to 10 carbon atom(s) and/or phenyl group(s);

B represents a heterocyclic ring of from 4 to 8 members containing one,two or three hetero atom(s) selected from the group consisting ofoxygen, nitrogen and sulphur atom(s), wherein the said ring mayoptionally be substituted by group(s) selected from oxo, thioxo and/orhydroxy group(s) including a ring of formula: ##STR18## T represents anoxygen atom or a sulphur atom; R¹ represents a group of general formula:##STR19## (iv) a straight or branched alkyl, alkenyl or alkynyl group offrom 1 to 20 carbon atom(s), wherein R⁵ and R⁶ independently represent ahydrogen atom or a halogen atom or a straight or branched alkyl, alkenylor alkynyl group of from 1 to 20 carbon atom(s) being unreplaced orreplaced by one, two, three, four or five optional carbon atom(s), byoxygen atom(s), sulphur atom(s), halogen atom(s), nitrogen atom(s),benzene ring(s), thiophene ring(s), naphthalene ring(s), carbocyclicring(s) of from 4 to 7 carbon atom(s), carbonyl group(s), carbonyloxygroup(s), hydroxy group(s), carboxy group(s), azido group(s) and/ornitro group(s);

R² represents a hydrogen atom or a straight or branched alkyl group offrom 1 to 6 carbon atom(s);

R³ represents a hydrogen atom, a halogen atom, a hydroxy group, a nitrogroup, a group of general formula: --COOR⁷, wherein R⁷ represents ahydrogen atom or a straight or branched alkyl group of from 1 to 6carbon atom(s), or a straight or branched alkyl, alkoxy or alkylthiogroup of from 1 to 6 carbon atom(s);

R⁴ represents a group of general formula: ##STR20## wherein U representsan oxygen atom or a sulphur atom, R⁸ represents a hydrogen atom or astraight or branched alkyl group of from 1 to 6 carbon atom(s), n and mrepresent an integer of from 1 to 10, respectively, p and q representzero or an integer of from 1 to 10, respectively, or non-toxic saltsthereof.

Representative compounds include:

7-(p-hexyloxybenzoyl)amino-2-(5-tetrazolyl)benzofuran,

7-(p-octyloxybenzoyl)amino-2-(5-tetrazolyl)benzofuran,

7-(p-heptyloxybenzoyl)amino-2-(5-tetrazolyl)benzofuran,

7-(p-nonyloxybenzoyl)amino-2-)5-tetrazoyly)benzofuran,

7-[p-(4-phenylbutoxy)benzoyl]amino-2-(5-tetrazolyl)-benzofuran,

7-[p-(2E,7,-octadienyl)benzoyl]amino-2-(5-tetrazolyl)-benzofuran,

7-[p-(6-chlorohexyloxy)benzoyl]amino-2-(5-tetrazolyl)-benzofuran and

7-(p-pentyicinnamoyl)amino-2-(5-tetrazolyl)benzofuran,

7-(p-hexyloxybenzoyl)amino-2-(5-tetrazolyl)-2,3-dihydro-1-benzofuran,

7-(p-heptyloxybenzoyl)amino-2-(5-tetrazolyl)-2,3-dihydro-1-benzofuran,

7-(p-octyloxybenzoyl)amino-2-(5-tetrazolyl)-2,3-dihydro-1-benzofuran,

7-(p-nonyloxybenzoyl)amino-2-(5-tetrazolyl)-2,3-dihydro-1-benzofuran,

7-(p-pentylcinnamoyl)amino-2-(5-tetrazolyl)-2,3-dihydro-1-benzofuran,

8[p-2E,7-octadienyloxy)benzoyl]amino-2-(5-tetrazolyl)quinoline,

8-[p-(4-phenylbutoxy)benzoyl]amino-2-(5-tetrazolyl)-quinoline,

8-[p-(6-chlorohexyloxy)benzoyl]amino-2-(5-tetrazolyl)-quinoline,

8-[p-(2E,7-octadienyloxy)benzoyl]amino-4-hydroxyquinoline-2-carboxylicacid,

8-[p-(4-phenylbutoxy)benzoyl]amino-4-hydroxyquinoline-2-carboxylic acid,

8-[p-[4-(2-thienyl)butoxy)benzoyl]amino-4-hydroxyquinoline-2-carboxylicacid,

8-[p-(2E,7-octadienyloxy)benzoyl]amino-4-hydroxy-2-(tetrazolyl)quinoline,

8-[p-(4-(2-phenylbutoxy)benzoyl]amino-4-hydroxy-2-(5-tetrazolyl)quinolineand,

8-(p-pentylcinnamoyl)amino-4-hydroxy-2-(5-tetrazolyl)quinoline and,

4-(p-heptyloxybenzoyl)amino-2-(5-tetrazolyl)-1,3-benzodioxole,

4-(p-hexyloxybenzoyl)amino-2-(5-tetrazolyl)-1,3-benzodioxole,

4-[p-[4-(phenylbutoxy)benzoyl]amino-2-(5-tetrazolyl)1,3-benzodioxole,

4-(p-pentylcinnamoyl)amino-2-(5-tetrazolyl)-1,3-benzodioxole,

9-[p-(4-phenylbutoxy)benzoyl]amino-2-(5-tetrazolyl)-3,4-dihydro-2H-1,5-benzodioxepin,

9-[p-(2E,7-octadienyloxy)benzoyl]amino-2-(5-tetrazolyl)-3,4-dihydro-2H-1,5-benzodioxepin,

9-[p-(7-octenyloxy)benzoyl]amino-2-(5-tetrazolyl)-3,4-dihydro-2H-1,5-benzodioxepin,

8-(p-heptyloxybenzoyl)amino-2-(5-tetrazolyl)-2,3-dihydro-1,4-benzoxazine,

8-[p-(4-phenylbutoxy)benzoyl]amino-2-(5-tetrazolyl)-2,3-dihydro-1,4-benzoxazineand

8-(p-pentylcinnamoyl)amino-2-(5-tetrazolyl)-2,3-dihydro-1,4-benzoxazine,

8-[p-(4-phenylbutoxy)benzoyl]amino-2-(5-tetrazolyl)-4-oxo-4H-1-benzothiopyran,

8-[p-(4-phenylbutoxy)benzol]amino-2-(5-tetrazolyl)-3,4-dihydro-2H-1-benzopyran,

8-[p-(7-octenyloxy)benzoyl]amino-2-(5-tetrazolyl)-3,4-dihydro-2H-1-benzopyran,

8-(p-pentylbenzoyl)amino-2-(5-tetrazolyl)-4-oxo-4H-1-benzopyran,

8-(p-pentylbenzoyl)amino-4-oxo-4H-1-benzopyran-2-carboxylic acid andethyl ester thereof,

8-(p-hexylbenzoyl)amino-2-(5-tetrazolyl)-4-oxo-4H-1-benzopyran,

8-(p-heptylbenzoyl)amino-2-(5-tetrazolyl)-4-oxo-4H-1-benzopyran,

8-(p-octylbenzoyl)amino-2-(5-tetrazolyl)-4-oxo-4H-1-benzopyran and

8-(p-nonylbenzoyl)amino-2-(5-tetrazolyl-4-oxo-4H-1-benzopyran

8-(p-butoxybenzoyl)amino-2-(5-tetrazolyl)-4-oxo-4H-1-benzopyran,

8-(p-pentyloxybenzoyl)amino-2-(5-tetrazolyl)-4-oxo-4H-1-benzopyran,

8-(p-hexyloxybenzoyl)amino-2-(5-tetrazolyl)-4-oxo-4H-1-benzopyran,

8-(p-heptyloxybenzoyl)amino-2-(5-tetrazolyl)-4-oxo-4H-1-benzopyran,

8-(p-nonyloxybenzoyl)amino-2-(5tetrazolyl)-4-oxo-4H-1-benzopyran,

8-(p-octyloxybenzoyl )amino-2-(5-tetrazolyl)-4-oxo-4H-1-benzopyran,

8-(p-heptyloxybenzoyl)amino-2-(5-tetrazolyl)-6-fluoro-4-oxo-4H-1-benzopyran

8-(p-octyloxybenzoyl)amino-2-(5-tetrazolyl)-6-methyl-4-oxo-4H-1-benzopyranand

8-(p-heptyloxybenzoyl)amino-2-(5-tetrazolyl)-6-methyl-4-oxo-4H-1-benzopyranand

8p-(2E,7-octadienyloxy)benzoyl]amino-2-(5-tetrazolyl)-4-oxo-4H-1-benzopyran

8-(p-geranyloxybenzoyl)amino-2-(5-tetrazolyl)-4-oxo-4H-1-benzopyran,

8p-(2E-nonenyloxy)benzoyl]amino-2-(5-tetrazolyl)-4-oxo-4H-1-benzopyran,

8[p-(2E-octenyloxy)benzoyl]amino-2-(5-tetrazolyl)-4-oxo-4H-1-benzopyran,

8[p-(7-octenyloxy)benzoyl]amino-2-(5-tetrazolyl)-4-oxo-4H-1-benzopyran,

8[p-(2E-heptenyloxy)benzoyl]amino-2-(5-tetrazolyl)-4-oxo-4H-1-benzopyran,

8[p-(2E-hexenyloxy)benzoyl]amino-2-(5-tetrazolyl)-4-oxo-4H-1-benzopyran,

8[p-(2E,7-octadienyloxy)benzoyl]amino-2-(5-tetrazolyl)-6-fluoro-4-oxo-4H-1-benzopyran,

8[p-(2E-octenyloxy)benzoyl]amino-2-(5-tetrazolyl)-6-methyl-4-oxo-4H-1-benzopyran,

8[p-(2E,7-octadienyloxy)benzoyl]amino-2-(5-tetrazolyl)-6-chloro-4-oxo-4H-1-benzopyran,

8[p-(2-octynyloxy)benzoyl]amino-2-(5-tetrazolyl)-4-oxo-4H-1-benzopyran,thereof

8[p-(4-chlorobutoxy)benzoyl]amino-2-(5-tetrazolyl)-4-oxo-4H-1-benzopyran,

8[p-(5-chloropentyloxy)benzoyl]amino-2-(5-tetrazolyl)-4-oxo-4H-1-benzopyran

8[p-(6-chlorohexyloxy)benzoyl]amino-2-(5-tetrazolyl)-4-oxo-4H-1-benzopyran,

8[p-(6-chlorohexyloxy)benzoyl]amino-2-(5-tetrazolyl)-4-oxo-4H-1-benzopyran,

8[p-(7-chloroheptyloxy)benzoyl]amino-2-(5-tetrazolyl)-4-oxo-4H-1-benzopyran

8[p-(8-chlorooctyloxy)benzoyl]amino-2-(5-tetrazolyl)-6-methyl-4-oxo-4H-1-benzopyran,

8[p-(7-chloroheptyloxy)benzoyl]amino-2-(5-tetrazolyl)-6-methyl-4-oxo-4H-1-benzopyranand

8[p-(8-chlorooctyloxy)benzoyl]amino-2-(5-tetrazolyl)-4-oxo-4H-1-benzopyran,

8[p-(3-phenylpropoxy)benzoyl]amino-2-(5-tetrazolyl)-4-oxo-4H-1-benzopyran,

8[p-(3-phenyl-2E-propenyloxy)benzoyl]amino-2-(5-tetrazolyl)-4-oxo-4H-1-benzopyran,

8[p-(4-phenylbutoxy)benzoyl]amino-2-(5-tetrazolyl)-4-oxo-4H-1-benzopyran,

8[p-(4-phenylbutoxy)benzoyl]amino-2-(5-tetrazolyl)-6-methyl-4-oxo-4H-1-benzopyran,

8[p-[2-(2-naphthy)ethoxy]benzoyl]amino-2-(5-tetrazolyl)-4-oxo-4H-1-benzopyran,

8[p-[2-(2-naphthyl)ethoxy])benzoyl]amino-2-(5-tetrazolyl)-6-methyl-4-oxo-4H-1-benzopyran,

8[p-[3-(3,4-dichlorophenyl)propoxy]benzoyl]amino-2-(5-tetrazolyl)-4-oxo-4H-1-benzopyran,

8[p-[3-(3,4-dichlorophenyl)propoxy]benzoyl]amino-2-(5-tetrazolyl)-4-oxo-4H-1-benzopyran,

8[p-[3-(p-chlorophenyl)butoxy]benzoyl]amino-2-(5-tetrazolyl)-4-oxo-4H-1-benzopyran,

8[p-[3-(p-chlorophenyl)butoxy]benzoyl]amino-6-methyl-2-(5-tetrazolyl)-4-oxo-4H-1-benzopyran,

8[p-[3-(p-chlorophenyl)propoxy]benzoyl]amino-6-methyl-2-(5-tetrazolyl)-4-oxo-4H-1-benzopyran,

8[p-[4-(2-thienyl)butoxy]benzoyl]amino-2-(5-tetrazolyl)-4-oxo-4H-1-benzopyran,

8[p-[4-(2-thienyl)butoxy]benzoyl]amino-2-(5-tetrazolyl)-6-methyl-4-oxo-4H-1-benzopyran,

8-(p-pentylcinnamoyl)amino-4-oxo-4H-1-benzopyran-2-carboxylic acid andmethyl ester thereof,

8-(p-pentylcinnamoyl)amino-2-(5-tetrazolyl)-4-oxo-4H-1-benzopyran,

8-(p-pentylcinnamoyl)amino-2-(5-tetrazolyl)-6-methyl-4-oxo-4H-1-benzopyran,

8-(p-pentylcinnamoyl)amino-2-(5-tetrazolyl)-6-fluoro-4-oxo-4H-1-benzopyran,

8-(p-pentylcinnamoyl)amino-6-methyl-4-oxo-4H-1-benzopyran-2-carboxylicacid and ethyl ester thereof,

8-(p-butylcinnamoyl)amino-2-(5-tetrazolyl)-4-oxo-4H-1-benzopyran,

8-(p-hexylcinnamoyl)amino-2-(5-tetrazolyl)-4-oxo-4H-1-benzopyran,

8-(p-heptylcinnamoyl)amino-2-(5-tetrazolyl)-4-oxo-4H-1-benzopyran,

8-cinnamoylamino-2-(5-tetrazolyl)-4-oxo-4H-1-benzopyran,

8-(p-hexyloxycinnamoyl)amino-2-(5-tetrazolyl)-4-oxo-4H-1-benzopyran,

8-(p-heptyloxycinnamoyl)amino-2-(5-tetrazolyl)-4-oxo-4H-1-benzopyran,

8-(p-isohexyloxycinnamoyl)amino-2-(5-tetrazolyl)-4-oxo-4H-1-benzopyran,

8[p-(2-octynyloxy)cinnamoyl]amino-4-oxo-4H-1-benzopyran-2-carboxylicacid,

8[p-(5-chloropentyloxy)cinnamoyl]amino-2-(5-tetrazolyl)-4-oxo-4H-1-benzopyran,

8[p-(6-chlorohexyloxy)cinnamoyl]amino-2-(5-tetrazolyl)-4-oxo-4H-1-benzopyran,

8-(p-pentylbenzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane;

8-(p-pentylbenzoyl)amino-2-(5-tetrazolyl)-6 chloro-1,4-benzodioxane;

8-(m-octylbenzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane;

8-(o-pentylbenzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane;

8-(p-butylbenzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane;

8-(p-hexylbenzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane;

8-(p-heptylbenzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane;

8-(p-octylbenzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane;

8-(p-nonylbenzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane;

8-(p-decylbenzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane;

8-(p-undecylbenzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane;

8-(p-dodecylbenzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane;

8-(p-pentyloxybenzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane;

8-(m-pentyloxybenzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane;

8-(o-pentyloxybenzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane;

8-(p-butyloxybenzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane;

8-(p-nonyloxybenzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane;

8-(p-propoxybenzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane;

8-(p-hexyloxybenzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane;

8-(p-heptyloxybenzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane;

8-(p-octyloxybenzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane;

8-(o-decyloxybenzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane;

8-(p-isopentyloxybenzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane;

8-(p-isohexyloxybenzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane;

8-[p-(1-methylbutoxy)benzoyl]amino-2-(5-tetrazolyl)-1,4-benzodioxane;

8-(N-methyl-N-(p-octynyloxy)benzoyl])amino-2-(5-tetrazolyl)-1,4-benzodioxane;

8-(p-octyloxybenzoyl)amino-1,4-benzodioxane-2-carboxylic acid and methylester thereof;

8-(p-isoheptyloxybenzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane;

8-(p-isooctyloxybenzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane;

8-[p-(3,7-dimethyloctyloxy)benzoyl]amino-2-(5-tetrazolyl)-1,4-benzodioxane;

8-(p-octyloxybenzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane-7-carboxylicacid,

8-[p-(2E-octyloxybenzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane,

8-[p-(3-butenyloxy)benzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane,

8-[p-(3Z-hexenyloxy)benzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane,

8-[p-(2Z-octenyloxy)benzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane,

8-[p-(2E-nonenyloxy)benzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane,

8-[N-methyl-N-[p-(2E-cctenyloxy)benzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane,

8-[p-(2E-hexenyloxy)benzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane,

8-[p-(3E-heptenyloxy)benzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane,

8-[p-(2E-octenyloxy)benzoyl)amino-1,4-benzodioxane-2-carboxylic acid andmethyl ester thereof,

8-[p-(2E-heptenyloxy)benzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane,

8-[p-(4-pentenyloxy)benzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane,

8-[p-(2E-decenyloxy)benzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane,

8-(p-geranyloxy)benzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane,

8-[p-(2E,7-octadienyloxy)benzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane,

8-[p-(2E-pentenyloxy)benzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane,

8-[p-(2E-butenyloxy)benzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane,

8-[p-(3E-octenyloxy)benzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane,

8-[p-(7-octenyloxy)benzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane,

8-[p-(2E,4E-octadienyloxy)benzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxaneand

8-[p-(2E-octadienyloxy)benzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane,

8-[p-(2-octynyloxy)benzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane,

8-[p-(2-octynyloxy)benzoyl]amino-1,4-benzodioxane-2-carboxylic acid andmethyl ester thereof and

8-[p-(2-isooctynyloxy)benzoyl]amino-2-(5-tetrazolyl)-1,4-benzodioxane

8-(p-pentylthiobenzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane,

8-(m-pentylthiobenzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane

8-(o-pentylthiobenzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane and

8-(p-heptylthiobenzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane

8-[p-(6-chlorohexyloxy)benzoyl]amino-2-(5-tetrazolyl)-1,4-benzodioxane,

8-[p-(5-chloropentyloxy)benzoyl]amino-2-(5-tetrazolyl)-1,4-benzodioxane,

8-[p-(4-chlorobutoxy)benzoyl]amino-2-(5-tetrazolyl)-1,4-benzodioxane,

8-[p-(7-chloroheptyloxy)benzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane,

8-[p-(8-chlorooctyloxy)benzoyl]amino-2-(5-tetrazolyl)-1,4-benzodioxane,

8-[p-(9-chlorononyloxy)benzoyl]amino-2-(5-tetrazolyl)-1,4-benzodioxaneand

8-[p-(t-bromopentyloxy)benzoyl]amino-2-(5-tetrazolyl)-1,4,-benzodioxane-2-carboxylicacid and methyl ester thereof

8-[p-hexyloxymethyl)benzoyl]amino-2-(5-tetrazolyl)-1,4-benzodioxane

8-[p-(cyclohexylmethoxy)benzoyl]amino-2-(5-tetrazolyl)-1,4-benzodioxane,

8-[p-(4-cyclohexylbutoxy)benozyl]amino-2-(5-tetrazolyl)-1,4-benzodioxane,and

8-[p-(2-cyclohexylethoxy)benzoyl')amino-2-(5-tetrazolyl)-1,4-benzodioxane,and

8-[p-(p-butylphenyl)methoxybenoyl]amino-2-(5-tetrazolyl)-1,4-benzodioxane,

8-[p-(5-phenylpentyloxy)benzoyl]amino-2-(5-tetrazolyl)-1,4-benzodioxane,

8-[p-(3-phenylpropoxy) benzoyl')amino-2-(5-tetrazolyl)-1,4-benzodioxane,

8-[p-(p-propylphenyl)methoxybenzoyl]amino-2-(5-tetrazolyl)-1,4-benzodioxane

8-[p-(3-phenyl-2-propenyloxy)benzoyl]amino-2-(5-tetrazolyl)-1,4-benzodioxane,

8-[p-(4-phenylbutoxy)benzoyl]amino-2-(5-tetrazolyl)-1, 4-benzodioxane,

8-[p-(o-pentylphenyl)methoxybenzoylamino-2-(5-tetrazolyl)-1,4-benzodioxane,

8-[p-(m-butylphenylmethoxybenzoyl]amino-2-(5-tetrazolyl)-1,4-benzodioxane,

8-(p-phenylmethoxybenzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane,

8-[p-(2-phenylethoxy)benzoyl')amino-2-(5-tetrazolyl)1,4-benzodioxane,

8-[p-4-phenylbutoxy)benzoyl]amino-2-(5-tetrazolyl)-1,4-benzodioxane,

8-[p[-2-(2-naphthyl)ethoxy]benzoyl')amino-2-(5-tetrazolyl)-1,4-benzodioxane

8-[p-[3-(p-chlorophenyl)propoxy]benzoyl]amino-2-(5-tetrazolyl)-1,4-benzodioxaneand

8-[p-[4-(p-chlorophenyl)butoxy]benzoyl]amino-2-(5-tetrazolyl)-1,4-benzodioxane,

8-[p-(5-methoxycarbonylpen,tyloxy)benzoyl]amino-2-(5-tetrazolyl)-1,4-benzodioxane,

8-[p-(6-acetyloxyhexyloxy)benzoyl]amino-2-(5-tetrazxolyl)-1,4-benzodioxane,

8-[p-(6-hydroxyhexyloxy)benzoyl]amino-2-(5-tetrazolyl)-1,4-benozdioxane,

8-[p-(2E-octenoyloxy)benzoyl]amino-2-(5-tetrazolyl)-1,4-benzodioxane and

8-(p-octanoylbenzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane

8-[p-(3-phenylthiopropoxy)benzoyl]amino-2-(5-tetrazolyl)-1,4-benzodioxane,

8-[p-(3-phenoxypropoxy)benzoyl]amino-2-(5-tetrazolyl)-1,4-benzodioxane,

8-[p-(2-phenylthioethoxy)benzoyl')amino-2-(5-tetrazolyl)-1,4-benzodioxaneand

8-[p-(2-phenoxyethoxy)benzoyl')amino-2-(5-tetrazolyl)-1,4-benzodioxane

8-[p-[2-(3-thienyl)ethoxy]benzoyl]amino-2-(5-tetrazolyl)-1,4-benzodioxaneand

8-[p-[4-(2-thienyl)butoxy]benzoyl')amino-2-(5-tetrazolyl)-1,4-benodioxane

8-[p-(5-azidopenyloxy)benozyl]amino-2-(5-tetrazolyl)-1,4-benzodioxane,

8-[p-(5-dimethylaminopentyloxy)benzoyl]amino-2-(5-tetrazolyl)-1,4-benzodioxane,

8-[p-(4-nitrobutoxy)benzoylamino-2-(5-tetrazolyl)-1,4-benzodioxane,

8-[p-(2-azidoethoxy)benzoyl]amino-2-(5-tetrazolyl)-1,4-benzodioxane,

8-[p-(4-azidobutoxy)benzoyl]amino-2-(5-tetrazolyl)-1,4-benzodioxane,

8-[p-(2-octenoylamino)benzoyl')amino-2-(5-tetrazolyl)-1,4-benzodioxane,

8-(p-pentyloxy-m-methoxybenzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane,

8-[p-(2E-octenyloxy)-m-chlorobenzoy]amino-2-(5-tetrazolyl)-1,4-benzodioxane

8-(2-naphthylcarbonyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane,

8-(p-pentylcinnamoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane,

8-(p-pentylcinnamoyl)amino-1,4-benzodioxane-2-carboxylic acid and methylester thereof,

8-(p-heptylcinnamoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane,

8-[N-methyl-[N-(pentylcinnamoyl)]amino]-2-(5-tetrazolyl)-1,4-benzodioxane,

5-(p-pentylcinnamoyl)amino-2-(5-tetrazolyl)-7-chloro-1,4-benzodioxane,

8-(p-pentylcinnamoyl)amino-2-(5-tetrazolyl)-6-chloro-1,4-benzodioxane,

8-(p-ethylcinnamoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane,

8-(p-propylcinnamoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane,

8-(p-butylcinnamoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane,

8-(p-pentylcinnamoyl)amino-2-(5-tetrazolyl)-6-methyl-1,4-benzodioxane,

8-(o-pentylcinnamoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane,

8-(m-octylcinnamoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane,

8-(p-pentylcinnamoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane-5-carboxylicacid and methyl ester thereof,

5-(p-pentylcinnamoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane-8-carboxylicacid and methyl ester thereof,

8-(p-hexylcinnamoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane,

8-(p-nonylcinnamoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane,

8-(p-pentylcinnamoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane-6-carboxylicacid and methyl ester thereof,

5-(p-pentylcinnamoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane-7-carboxylicacid and methyl ester thereof,

8-(p-octylcinnamoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane,

8-(p-decylcinnamoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane,

8-P-isopropylcinnamoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane,

8-(p-isobutylcinnamoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane,

8-(p-isopentylcinnamoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane,

8-(p-pentyl-2-methylcinnamoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane,

8-(p-pentyl-3-methylcinnamoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxaneand

8-(p-pentylcinnamoyl)amino-2-(5-tetrazolyl)methyl-1,4-benzodioxane

8-(p-pentyloxycinnamoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane,

8-(m-pentyloxycinnamoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane,

8-(o-pentyloxycinnamoyl)amino-2-(5-tetrazoly)-1,4-benzodioxane,

8-(p-propoxycinnamoyl)amino-2-(5-tetrazolyl)-1,4,-benzodioxane,

8-(p-butoxycinnamoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane,

8-(p-octyloxycinnamoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane,

8-(p-hexyloxycinnamoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane,

8-(p-heptyloxycinnamoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane,

8-(p-isopentyloxycinnamoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane,

8-(p-isohexyloxycinnamoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane,

8-[p-(1-methylbutoxy)cinnamoyl]amino-2-(5-tetrazolyl)-1,4-benzodioxane,

8-(p-isoheptyloxycinnamoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane,

8-(p-isooctyloxycinnamoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane,

8-(p-isohexyloxy-2-methylcinnamoyl)amino-2-(5-tetra-zolyl)-1,4-benzodioxaneand

8-(p-isohexyloxy-2-phenylcinnamoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane,

8-[p-(2E-octenyloxy)cinnamoyl]amino-2-(5-tetrazolyl)-1,4-benzodioxane,

8-[p-(2-propenyloxy)cinnamoyl]amino-2-(5-tetrazolyl)-1,4-benzodioxane,

8-[p-(3-butenyloxy)cinnamoyl]amino-2-(5-tetrazolyl)-1,4-benzodioxane,

8-[p-(3Z-hexenyloxy)cinnamoyl]amino-2-(5-tetrazolyl)1,4-benzodioxane,

8-[p-2Z-pentenyloxycinnamoyl]amino-2-(5-tetrazolyl)-1,4-benzodioxane,

8-[p-(2E-nonenyloxy)cinnamoyl]amino-2-(5-tetrazolyl)-1,4-benzodioxane,

8-[p-(3E-heptenyloxy)cinnamoyl]amino-2-(5-tetrazolyl)-1,4-benzodioxane,

8-[p-(2E-heptenyloxy)cinnamoyl]amino-2-(5-tetrazolyl)-1,4-benzodioxane,

8-[p-(2E-hexenyloxy)cinnamoyl]amino-2-(5-tetrazolyl)-1,4-benzodioxane,

8-[p-(2E-pentenyloxy)cinnamoyl]amino-2-(5-tetrazolyl)1,4-benzodioxane,

8-[p-(4-pentenyloxy)cinnamoyl]amino-2-(5-tetrazolyl)1,4-benzodioxane,

8-[p-(2E-butenyloxy)cinnamoyl]amino-2-(5-tetrazolyl)-1,4-benzodioxaneand

8-[p-(2E-decenyloxy)cinnamoyl]amino-2-(5-tetrazolyl)-1,4-benzodioxane

8-[p-(2-octynyloxy)cinnamoyl]amino-2-(5-tetrazolyl)-1,4-benzodioxane and

8-[p-(2-pentynyloxy)cinnamoyl]amino-2-(5-tetrazolyl)-1,4-benzodioxane,

8-(p-pentylthiocinnamoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane,

8-(m-pentylthiocinnamoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane and

8-(o-pentylthiocinnamoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane,

8-[p-(6-chlorohexyloxy)cinnamoyl]amino-2-(5-tetrazolyl)1,4-benzodioxane,

8-[p-(4-chlorobutoxy)cinnamoyl]amino-2-(5-tetrazolyl)-1,4-benzodioxane,

8-[p-(5-chloropentyloxy)cinnamoyl]amino-2-(5-tetrazolyl)-1,4-benzodioxaneand

8-[p-(7-chloroheptyloxy)cinnamoyl')amino-2-(5-tetrazolyl)-1,4-benzodioxane

8-(p-isopentyloxymethyl-cinnamoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane,

8-(p-cyclohexylcinnamoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane,

8-(p-cyclohexylmethoxycinnamoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane,

8-[p-(4-cyclohexylbutoxy)cinnamoyl')amino-2-(5-tetrazolyl)-1,4-benzodioxaneand

8-[p-(2-cyclohexylethoxy)cinnamoyl]amino-2-(5-tetrazolyl)-1,4-benzodioxane,

8-(p-phenylmethylcinnamoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane,

8-(p-phenylmethoxycinnamoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane,

8-[p-(2-phenylethoxy)cinnamoyl]amino-2-(5-tetrazolyl)-1,4-benzodioxane,

8-[p-(4-phenylbutoxy)cinnamoyl]amino-2-(5-tetrazolyl)-1,4-benzodioxane,

8-[p-(5-phenylpentyloxy)cinnamoyl]amino-2-(5-tetrazolyl)-1,4-benzodioxaneand

8-[p-(3-phenylpropoxy)cinnamoyl]amino-2-(5-tetrazolyl)-1,4-benzodioxane,

8-[p-(6-acetyloxyhexyloxy)cinnamoyl]amino-2-(5-tetrazolyl)-1,4-benzodioxane

8-[p-[2-(2-thienyl)ethoxy)-cinnamoyl]-amino-2-(5-tetrazolyl)-1,4-benzodioxane,

8-(m,p-dimethoxycinnamoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane,

8-(m-methoxy-p-pentyloxycinnamoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxaneand

8-(p-pentyloxy-m-chlorocinnamoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane

8-[3-(5-indanyl)acryloyl]amino-2-(5-tetrazolyl)-1,4-benzodioxane,

N-(2-hexadecenoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane,

8-(p-pentylphenylacetyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane and

8-[3-(p-pentylphenyl)propionyl]amino-2-(5-tetrazolyl)-1,4-benzodioxane

8-(p-hexylphenylpropioloyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane,

8-[5-(p-propoxyphenyl)penta-2E,4E-dienoyl]amino-2-(5-tetrazolyl)-1,4-benzodioxaneand

8-[5-(p-butylphenyl)penta-2E,4E-dienoyl]amino-2-(5-tetrazolyl)-1,4-benzodioxane,

8-(p-pentylcinnamoyl)amino-2-(5-tetrazolyl)-2,3-dihydro-14-dithianaphthaleneand

5-(p-pentylcinnamoyl)amino-2-(5-tetrazolyl)-2,3-dihydro-1,4-dithianaphthaleneand sodium salts thereof.

Also included are aromatic 1,2-di(thio)ethers of the formula: ##STR21##wherein A is an 1,2-disubstituted aromatic ring; preferably a benzenering;

wherein

X is independently O, S, SO, or SO₂ ;

R is H,

C₁ -C₄ alkyl,

phenyl or substituted phenyl,

halo,

haloalkyl,

hydroxy,

carboxy,

cyano,

C₁ -C₄ alkoxy,

C₁ -C₄ alkylthio,

C₁ -C₄ alkylsulfinyl,

C₁ -C₄ alkylsulfonyl,

nitro,

amino,

C₁ -C₄ mono or di-alkylamino;

R' and R" are independently

H,

halo,

C₁ -C₄ alkyl or C₁ -C₄ alkoxy,

amino, or oxo, where CH--R' or CH--R" in the formula become --C═O;

y is 1-6;

z is 6-20; and

wherein ##STR22## can independently represent substituted orunsubstituted alkyl radicals or alkenyl radicals containing at least onealkene bond;

and pharmaceutically acceptable salts and esters thereof.

The compounds of the instant invention are inhibitors of the humantestosterone-5α-reductase enzyme.

The scope of the compounds of the instant invention are described by theabove-described formula.

In the description of the formula the following terms are used which arehereby defined:

X in the general formula above is O or S, preferably where one X is O,and particularly where both Xs are O, e.g., resulting in the catecholstructure.

"C₁ -C₄ alkyl" includes linear or branched species, e.g. methyl, ethyl,n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, t-butyl.

"C₁ -C₄ alkoxy" includes linear or branched species, e.g., methoxy,ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy,t-butoxy.

"Halo" includes fluoro, chloro, bromo or iodo.

"Substituted phenyl" includes phenyl substituted by one or more of C₁-C₄ alkyl, C₁ -C₄ alkoxy, or halo, and the like, as defined above.representative examples include o, m-, p-methoxy phenyl;2,4-dimethoxyphenyl; 2-chloro-4-ethoxyphenyl; 3,5-dimethoxyphenyl;2,4-dichlorophenyl; 2-bromo-4-methylphenyl, o-fluorophenyl, and thelike.

"Haloalkyl" includes C₁ -C₄ alkyl, defined above, substitued with one ormore "halo" as defined above and includes: trifluoromethyl,2,2-dichloroethyl and the like.

"C₁ -C₄ alkylthio" includes C₁ -C₄ alkyl, defined above, substitutedwith at least one divalent thio (--S--) grouping including; methylthio,ethylthio, isopropylthio, n-butylthio, and the like.

"C₁ -C₄ alkylsulfinyl" includes C₁ -C₄ alkyl, defined above, substitutedwith at least one --SO-- grouping including; methylsulfinyl,ethylsulfinyl; isopropylsulfinyl, and the like.

"C₁ -C₄ alkylsulfonyl" includes C₁ -C₄ alkyl, defined above, substitutedwith at least one sulfonyl group, --SO₂ --, including; methylsulfonyl,ethylsulfonyl, isopropylsulfonyl, n-butylsulfonyl, and the like.

"C₁ -C₄ mono or dialkyl amino" includes amino, substituted with one ormore C₁ -C₄ alkyl groups as defined hereinabove, including: methylamino,ethylamino, n-butylamino, t-butylamino, N,N-dimethylamino,N,N-diethylamino, methyl-t-butylamino, and the like.

The R group or groups on the benzene ring can be present initially inthe process, such as in starting material I in Flow Chart A, e.g.phenyl, methyl, methoxy, cyano, trifluoromethyl, carbomethoxy, or addedlater by a conventional reaction, e.g. chloro, as by chlorination, nitroby nitration, or created from a starting or added functional grouppresent, e.g. converting a nitro to an amino group by catalyticreduction, then alkylating to a mono or dialkylamine. An amino group canbe subjected to diazotization to a hydroxy group, which can be followedby methylation to a methoxy group. Similarly, a hydroxy group can beconverted to a thiol by the analogous procedures described in J. Org.Chem. 31, pp 3980-3984 (1966) by Newman and Karnes, and J. Org. Chem.31, pp 410 (1966) by Kwart, H. and Evans, E. S. The resulting thiol canbe alkylated to alkylthio, which can be oxidized to the correspondingsulfoxide or sulfone. Preferred substituents are H, C₁ -C₄ alkyl, C₁ -C₄alkoxy and phenyl. These reactions and sequences are conventional in theart and it will be obvious to one skilled in the art to modify thebenzene ring to arrive at an R radical disclosed herein.

By the term "pharmaceutically acceptable salts and esters thereof" ismeant, salts and esters of the acid groups in the final molecule whichcan be used as part of the human drug delivery system and include thesalts: sodium, potassium, calcium, ammonium, substituted ammonium,quaternary ammonium, and esters: ethyl ester, aceturate, besylate,edetate, phenpropionate, acetate, pamoate, and esters which serye as"prodrug" formulations which will hydrolyze in the body at physiologicalpH's to regenerate the acid, including pivaloylates, e.g. pivoxetil andpivoxil, and Kanebo esters, and the like. ##STR23## where y is 1-6,preferably 3, can contain at least one R' substituent as defined above,and can be, e.g., ##STR24## and the like.

An alkene bond can also be present in R' ##STR25## and the like.##STR26## where z is 6-20, preferably 10-16, can contain at least one R"substituent as defined above, and can be; e.g., ##STR27## and the like.

An alkene bond can also be present in ##STR28## e.g., CH₂--CH═CH--(CH₂)₈ --; --(CH₂)₈ --CH═CH(CH₂)₂ --; --(CH₂)₉ --CH═CH--(CH₂)₉--; (CH₂)₄ --CH═CH--(CH₂)₄ --; and the like.

R' and R" can also be --NHCOCH₃, which can be hydrolyzed to amino byconventional acid or base hydrolysis in the final molecule; R' and R"can also be oxo, obtained by, for example, HBr addition to an alkenefollowed by conversion to an alcohol and subsequent oxidation to theketone.

Preferred is where one R' or R" is H and particularly preferred is whereboth ##STR29## are alkyl.

Preferred compounds of the instant invention are given by the followingformulas; ##STR30## wherein one X is O and R, R', R", y and z aredefined above; and particularly preferred are the compounds, ##STR31##wherein X is O or S and n is 10-16.

The compounds of the instant invention can be made by the procedureoutlined in the following Flowchart A-1. ##STR32##

As seen in Flow Chart A-1, Compound I is the starting substrate in theinvention process and is a 1,2-substituted benzene ring. X can beindependently O or S and "PG" represents a hydroxy or thio protectinggroup which is inactive during Step (A) but can be subsequently removedby, e.g. palladium on carbon catalyst in ethanol under a pressurized H₂atmosphere.

Examples of "PG" protecting groups which are conventional and known inthe art (See "Protective Groups in Organic Synthesis" by Theodora W.Greene--1981 --John Wiley--Chapter 2, "Protection for the HydroxylGroup, Including 1,2- and 1,3-Diols" pp. 16-87 and Chapter 6 "Protectionfor the Thiol Group" pp. 193-218).

Representative examples of "PG" include: benzyl, p-methoxybenzyl,p-halobenzyl; including p-chlorobenzyl, p-fluorobenzyl, and the like.Other protective groups which are known will be obvious to one skilledin the art to carry out the function of Step (A).

Representive examples of compounds useful as I in the instant invention,include, but are not limited to the following:

2-(benzyloxy)-phenol,

2-benzyloxy-thiophenol,

2-(benzylthio)-phehol,

2-(benzylthio)thiophenol,

3-methoxy-2-benzyloxyphenol,

2-benzyloxy-4-methoxyphenol,

3-methyl-2-benzyloxyphenol,

2-benzyloxy-5-methylphenol,

2-benzyloxy-4-methylphenol,

2-benzyloxy-5-methylphenol,

2-benzyloxy-3,5-diisopropylphenol,

2-benzyloxy-3,5-di-t-butylphenol,

2-benzyloxy-4-t-butylphenol,

2-benzyloxy-3-ethylphenol,

2-benzyloxy-5-phenylphenol,

2-benzyloxy-4-methyl-1-thiophenol,

2-benzyloxy-5-trifluoromethyl-1-thiophenol,

2-benzyloxy-6-methoxy-1-thiophenol,

2-benzylthio-4-methyl-thiophenol,

2-benzylthio-5-methylsulfonyl-phenol, and the like.

Representative examples of II useful in the invention process where L isa leaving group, e.g., halogen, including bromo, chloro, or sulfonate,and the like, and R^(a) is a C₁ -C₄ linear or branched alkyl portion ofthe ester, including methyl, ethyl, isopropyl, t-butyl, sec-butyl, andthe like, and where R¹ and Y are or defined above, include, but are notlimited to:

Br--CH₂ --COOMe,

Cl--CH₂ CH₂ CH₂ COOCH₂ CH₃,

Br--CH₂ CH₂ CH₂ CH₂ COOMe,

Br--CH₂ CH₂ CH₂ CH₂ CH₂ COOEt,

Br--CH₂ CH₂ CH₂ CH₂ CH₂ CH₂ COOCH₂ CH₂ CH₂ CH₃,

Br--(CH₂)₂ CH(CH₃)COOMe,

Br--CH₂ CH(CH₃)CH₂ COOEt,

Br--CH₂ CH₂ CH₂ COOMe,

Br--CH₂ CH(OCH₃)CH₂ COOCH(CH₃)₂,

Cl--CH₂ CH(OCH₂ CH₃)CH₂ COOMe,

Br--CH₂ CH(F)CH₂ COOMe,

Cl--CH₂ CH₂ COOEt,

and the like.

In Step (A) the condensation of I and II to produce III takes place inan non-hydroxylated polar organic solvent, e.g., acetone, ethyl acetate,methylethylketone, dioxan, THF, diethylketone, and the like, A protonacceptor is also present, e.g. potassium carbonate, sodium bicarbonate,pyridine, triethylamine, and the like. Generally, the reaction iscarried out under an inert atomosphere, e.g. dry nitrogen, and heated atreflux or allowed to sit for an extended period of time at roomtemperature. Workup is conventional.

In Step (B) the protecting group, "PG", is catalytically removed atambient temperature under a pressurized, hydrogen atmosphere in anorganic solvent to produce IV, being a phenol or thiophenol. Operablecatalysts include 5% Pd/C, and the like. The organic solvent should beinert under the reaction conditions and includes ethyl acetate, ethanol,methanol, dioxane, and the like.

Step (C) involves reacting IV with V to produce VI, the diester. Thereaction conditions are similar to those described in Step (A) utilizingan inert organic solvent for the reactants and a proton acceptor.

Representative examples of V useful in the invention are:

Br(CH₂)₆ COOMe,

Br(CH₂)₇ COOMe,

Br(CH₂)₈ COOMe,

Br(CH₂)₉ COOMe,

Br(CH₂)₁₀ COOMe,

Br(CH₂)₁₁ COOMe,

Cl(CH₂)₁₂ COOEt,

Cl(CH₂)₁₃ COOCH(CH₃)₂,

Cl(CH₂)₁₄ COOCH₂ CH₂ CH₃,

Br--(CH₂)₁₅ COOMe

Br--(CH₂)₁₆ COOMe

Br(CH₂)₁₆ COOCH₂ CH₃,

Br(CH₂)₁₇ COOC(CH₃)₃,

Br(CH₂)₁₈ COOMe,

Br(CH₂)₁₉ COOEt,

Br(CH₂)₂₀ COOMe,

Br(CH₂)₂ CH(CH₃)--(CH₂)₁₀ COOMe,

Br--CH₂ CH(CH₃)(CH₂)₁₀ COOMe,

Br--CH₂ CH₃ CH(CH₃)CH₂ COOEt,

Br--CH₂ CH(OCH₃)(CH₂)₇ COOCH(CH₃)₂,

Cl--CH₂ CH(OCH₂ CH₃)CH₂ CH₂ COOMe,

Br--CH₂ CH(NHCOCH₃)--(CH₂)₁₀ --CH₂ --COOMe, ##STR33## Br--CH₂ --(CH₂)₉--CH═CH--COOMe, and the like.

In Step (D), the diester can be deesterified by aqueous basichydrolysis, e.g. NaOH in MeOH/H₂ O to yield the diacid VII uponacidification. ##STR34##

Flow Sheet B-1 illustrates the specific synthesis of 7.

As seen, 2-benzyloxyphenol 1, ethyl 4-bromobutyrate 2 and anhydrous K₂CO₃ in e.g., dry acetone are heated at reflux or stirred for an extendedperiod of time at room temperature, under a nitrogen atmosphere to giveproduct ethyl 4-(2-benzyloxyphenoxy) butyrate 3, in Step (A).

A solution of 3 in e.g., ethyl acetate is catalytically hydrogenated atroom temperature under e.g. 40 psig of H₂ in the presence of a 5% Pd/Ccatalyst to yield ethyl 4-(2-hydroxyphenoxy) butyrate 4 in Step (B).

Step (C) comprises reacting 4 and methyl 12-bromododecanoate 5 withpotassium carbonate in acetone as in Step (A) to obtain the monomethylester 6.

In Step (D), the diester 6 is de-esterified by e.g., 2.5 N NaOH inMeOH/H₂ O to yield the final product, diacid 7, upon acidification.

Flow Sheet C-1 illustrates the synthesis of the sulfur analog of 7 as7A. This analogous procedure uses substantially the same steps asinvolved in Flow Sheet B.

It is also obvious from the above Flow Sheets that suitable replacementcompounds for II and 2 with other substituted and unsubstituted haloalkyl esters, known in the art and described herein, and that suitablereplacement of V and 5 with other bromoesters, available in the art andalso described above will yield all of the compounds within the scope ofthe instant claims.

Representative examples of compounds produced by this process include:

4-(2-(20-Carboxyeicosyloxy)phenoxy)butyric acid;

4-(2-(19-Carboxynonadecyloxy)phenoxy)butyric acid;

4-(2-(18-Carboxyoctadecyloxy)phenoxy)butyric acid;

4-(2-(17-Carboxyheptadecyloxy)phenoxy)butyric acid;

4-(2-(16-Carboxyhexadecyloxy)phenoxy)butyric acid;

4-(2-(15-Carboxypentadecyloxy)phenoxy)butyric acid;

4-(2-(14-Carboxytetradecyloxy)phenoxy)butyric acid;

4-(2-(13-Carboxytridecyloxy)phenoxy)butyric acid;

4-(2-(12-Carboxydodecyloxy)phenoxy)butyric acid;

4-(2-(11-Carboxyundecyloxy)phenoxy)butyric acid;

4-(2-(10-Carboxydecyloxy)phenoxy)butyric acid;

4-(2-(9-Carboxynqnyloxy)phenoxy)butyric acid;

4-(2-(8-Carboxyoctyloxy)phenoxy)butyric acid;

4-(2-(7-Carboxyheptyloxy)phenoxy)butyric acid;

4-(2-(6-Carboxyhexyloxy)phenoxy)butyric acid;

4-(2-(20-Carboxyeicosyloxy)phenylthio)butyric acid;

4-(2-(19-Carboxynonadecyloxy)phenylthio)butyric acid;

4-(2-(18-Carboxyoctadecyloxy)phenylthio)butyric acid;

4-(2-(17-Carboxyheptadecyloxy)phenylthio)butyric acid;

4-(2-(16-Carboxyhexadecyloxy)phenylthio)butyric acid;

4-(2-(15-Carboxypentadecyloxy)phenylthio)butyric acid;

4-(2-(14-Carboxytetradecyloxy)phenylthio)butyric acid;

4-(2-(13-Carboxytridecyloxy)phenylthio)butyric acid;

4-(2-(12-Carboxydodecyloxy)phenylthio)butyric acid;

4-(2-(11-Carboxyundecyloxy)phenylthio)butyric acid;

4-(2-(10-Carboxydecyloxy)phenylthio)butyric acid;

4-(2-(9-Carboxynonyloxy)phenylthio)butyric acid;

4-(2-(8-Carboxyoctyloxy)phenylthio)butyric acid;

4-(2-(7-Carboxyheptyloxy)phenylthio)butyric acid;

4-(2-(6-Carboxyhexyloxy)phenylthio)butyric acid;

4-(2-(20-Carboxyeicosylthio)phenoxy)butyric acid;

4-(2-(19-Carboxynonadecylthio)phenoxy)butyric acid;

4-(2-(18-Carboxyoctadecylthio)phenoxy)butyric acid;

4-(2-(17-Carboxyheptadecylthio)phenoxy)butyric acid;

4-(2-(16-Carboxyhexadecylthio)phenoxy)butyric acid;

4-(2-(15-Carboxypentadecylthio)phenoxy)butyric acid;

4-(2-(14-Carboxytetradecylthio)phenoxy)butyric acid;

4-(2-(13-Carboxytridecylthio)phenoxy)butyric acid;

4-(2-(12-Carboxydodecylthio)phenoxy)butyric acid;

4-(2-(11-Carboxyundecylthio)phenoxy)butyric acid;

4-(2-(10-Carboxydecylthio)phenoxy)butyric acid;

4-(2-(9-Carboxynonylthio)phenoxy)butyric acid;

4-(2-(8-Carboxyoctylthio)phenoxy)butyric acid;

4-(2-(7-Carboxyheptylthio)phenoxy)butyric acid;

4-(2-(6-Carboxyhexylthio)phenoxy)butyric acid;

4-(2-(20-Carboxyeicosylthio)phenylthio)butyric acid;

4-(2-(19-Carboxynonadecylthio)phenylthio)butyric acid;

4-(2-(18-Carboxyoctadecylthio)phenylthio)butyric acid;

4-(2-(17-Carboxyheptadecylthio)phenylthio)butyric acid;

4-(2-(16-Carboxyhexadecylthio)phenylthio)butyric acid;

4-(2-(15-Carboxypentadecylthio)phenylthio)butyric acid;

4-(2-(14-Carboxytetradecylthio)phenylthio)butyric acid;

4-(2-(13-Carboxytridecylthio)phenylthio)butyric acid;

4-(2-(12-Carboxydodecylthio)phenylthio)butyric acid;

4-(2-(11-Carboxyundecylthio)phenylthio)butyric acid;

4-(2-(10-Carboxydecylthio)phenylthio)butyric acid;

4-(2-(9-Carboxynonylthio)phenylthio)butyric acid;

4-(2-(8-Carboxyoctylthio)phenylthio)butyric acid;

4-(2-(7-Carboxyheptylthio)phenylthio)butyric acid;

4-(2-(6-Carboxyhexylthio)phenylthio)butyric acid;

3-(2-(16-Carboxyhexadecyloxy)phenoxy)propionic acid;

3-(2-(15-Carboxyisohexadecyloxy)phenoxy)butyric acid;

3-(2-(14-Carboxytetradecyloxy)phenoxy)butyric acid;

5-(2-(13-Carboxytridecyloxy)phenoxy)valeric acid;

5-(2-(12-Carboxydodecyloxy)phenoxy)valeric acid;

5-(2-(11-Carboxyisododecyloxy)phenoxy)valeric acid;

4-(2-(11-Carboxyundecyloxy)phenoxy)valeric acid;

4-(2-(10-Carboxydecyloxy)phenoxy)valeric acid;

4-(2-(9-Carboxynonyloxy)phenoxy)valeric acid;

6-(2-(9-Carboxynonyloxy)phenoxy)caproic acid;

6-(2-(8-Carboxyoctyloxy)phenoxy)caproic acid;

6-(2-(7-Carboxyisooctyloxy)phenoxy)caproic acid;

7-(2-(7-Carboxyheptyloxy)phenoxy)enanthic acid;

7-(2-(6-Carboxyhexyloxy)phenoxy)enanthic acid;

7-(2-(5-Carboxyisohexyloxy)phenoxy)enanthic acid;

2-(2-(12-Carboxydodecylthio)phenoxy)acetic acid;

2-(2-(11-Carboxydecylthio)phenoxy)acetic acid;

2-(2-(10-Carboxydecylthio)phenoxy)acetic acid;

3-(2-(9-Carboxynonyloxy)phenylthio)propionic acid;

3-(2-(12-Carboxydodecyloxy)phenylthio)propionic acid;

3-(2-(11-Carboxyundecyloxy)phenylthio)propionic acid;

3-(2-(11-Carboxyundecyloxy)phenylthio)butyric acid;

3-(2-(11-Carboxyundecylthio)-4-methyl-phenylthio)butyric acid;

3-(2-(12-Carboxydodecylthio)phenylthio)butyric acid;

5-(2-(11-Carboxyundecylthio)phenylthio)valeric acid;

5-(2-(10-Carboxydecyloxy)phenylthio)valeric acid;

5-(2-(9-Carboxynonyloxy)phenylthio)valeric acid;

3-(2-(12-Carboxydodecyloxy)phenylthio)valeric acid;

3-(2-(11-Carboxydecyloxy)phenylthio)valeric acid;

3-(2-(10-Carboxydecyloxy)phenylthio)valeric acid;

6-(2-(9-Carboxynonylthio)phenylthio)caproic acid;

6-(2-(12-Carboxydodecyloxy)phenylthio)caproic acid;

6-(2-(11-Carboxyundecyloxy)phenylthio)caproic acid;

6-(2-(11-Carboxyundecyloxy)-3-methylphenylthio)-enanthic acid;

7-(2-(11-Carboxyundecyloxy)-4-methylphenylthio)-enanthic acid;

7-(2-(12-Carboxydodecylthio)phenoxy)enanthic acid;

4-(2-(11-Carboxyundecyloxy)4-methyl-phenoxy)butyric acid;

4-(2-(10-Carboxydecyloxy)3-methylphenoxy)butyric acid;

4-(2-(9-Carboxynonyloxy)5-methylphenoxy)butyric acid;

4-(2-(12-Carboxydodecyloxy)6-methylphenoxy)butyric acid;

4-(2-(12-Carboxydodecyloxy)6-methylphenoxy)butyric acid;

4-(2-(11-Carboxyundecylthio)-3-(methylthio)phenoxy)-valeric acid;

4-(2-(11-Carboxyundecylthio)-3-(methylsulfonyl)phenoxy)butyric acid;

4-(2-(11-Carboxyundecyloxy)-4-(methylsulfonyl)phenoxy)butyric acid;

4-(2-(12-Carboxydodecyloxy)5-ethyl-phenoxy)butyric acid;

4-(2-(11-Carboxyundecyloxy)4-phenylphenoxy)butyric acid;

4-(2-(10-Carboxydecyloxy)-3,5-dimethylphenoxy)butyric acid;

4-(2-(9-Carboxynonyloxy)-4-fluoro-phenoxy)butyric acid;

4-(2-(12-Carboxydodecyloxy)-5-(trifluoromethyl)-phenoy)butyric acid;

4-(2-(12-Carboxydodecylthio)-5-nitrophenoxy)butyric acid;

4-(2-(11-Carboxyundecylthio)-4-methylphenoxy)valeric acid;

4-(2-(11-Carboxyundecylthio)-3,5-di-methylphenoxy)-butyric acid;

4-(2-(12-Carboxydodecyloxy)-4-(dimethylamino)phenoxy)-butyric acid;

4-(2-(11-Carboxyundecyloxy)-5-(ethylamino)phenoxy)-butyric acid;

2-(2-(9-Carboxynonyloxy)phenoxy)propionic acid;

3-(2-(12-Carboxydodecyloxy)phenoxy)-3-methylpropionic acid;

4-(2-(10-Carboxydecyloxy)phenylthio)-3-methoxy-butyric acid;

4-(2-(9-Carboxynonyloxy)phenylthio)-3-ethoxy-butyric acid;

4-(2-(11-Carboxyundecyloxy)phenoxy)but-2-enoic acid;

4-(2-(9-Carboxynonyloxy)phenoxy)-2-butenoic acid;

4-(2-(11-Carboxy-2-methylundecyloxy)phenoxy)butyric acid;

4-(2-(11-Carboxyundecyl-7-ene-oxy)phenoxy)butyric acid;

4-(2-(13-Carboxy-2-methylene-tri-decyloxy)phenoxy)-butyric acid;

4-(2-(11-Carboxyundecyloxy)phenylsulfonyl)butyric acid;

4-(2-(11-Carboxyundecyloxy)phenylsulfinyl)butyric acid;

4-(2-(11-Carboxyundecylsulfinyl)phenoxy)butyric acid;

4-(2-(11-Carboxyundecylsulfonyl)phenoxy)butyric acid;

4-(2-(11-Carboxyundecylsulfinyl)phenylsulfinyl)butyric acid;

4-(2-(11-Carboxyundecylsulfonyl)phenylsulfonyl)butyric acid; and thelike.

Also included as a 5α-reductase inhibitor in this invention is an agentfor the treatment of prostatic cancer in combination with flutamide isof the following formula: ##STR35## wherein A is an 1,2-disubstitutedaromatic ring selected from

(a) benzene, 1,2-disubstituted naphthalene;

(b) 5-6 membered heteroaromatic ring, containing 1-2 N atoms, 1 S or 0atom, or combination thereof;

D and E are independently --COOH, --CONH₂, CONHR_(b), COOR_(b), SO₂ OH,SO₃ (OH), SO₂ NH₂, --SSO₂ ONa, PH(O)(OH), P(O)(OH)₂ ;

X is O, S, SO or SO₂ ;

R is H,

C₁ -C₄ alkyl,

phenyl or substituted phenyl,

halo,

haloalkyl,

hydroxy,

carboxy,

cyano,

C₁ -C₄ alkoxy,

C₁ -C₄ alkylthio,

C₁ -C₄ alkylsulfinyl,

C₁ -C₄ alkylsulfonyl,

nitro,

amino,

C₁ -C₄ mono or di-alkylamino;

R' and R" are independently

H

halo,

C₁ -C₄ alkyl or C₁ -C₄ alkoxy,

amino, or oxo, where CH--R' or CH--R" in the formula become --C═O;

R_(a) is H, C₁ -C₄ alkyl;

R_(b) is C₁ -C₁₂ alkyl, phenyl or phenyl C₁ -C₄ alkyl;

y is 1-6;

z is 6-20; and

wherein ##STR36## can independently represent substituted orunsubstituted alkyl radicals or alkenyl radicals containing at least onealkene bond;

and pharmaceutically acceptable salts and esters thereof.

The compounds of the instant invention are inhibitors of the humantestosterone-5α-reductase

The scope of the compounds of the instant invention are described by theabove-described formula.

In the description of the formula the following terms are used which arehereby defined:

X is preferably O or S, and particularly preferred is O.

"C₁ -C₄ alkyl" includes linear or branched species, e.g. methyl, ethyl,n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, t-butyland "C₁ -C₁₂ alkyl" includes, alkyl up to 12 cartons including n-octyl,t-decyl, n-dodecyl.

"Phenyl C₁ -C₄ alkyl" includes benzyl, 2-phenethyl and the like.

"C₁ -C₄ alkoxy" includes linear or branched species, e.g., methoxy,ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy,t-butoxy.

"Halo" includes fluoro, chloro, bromo or iodo.

By the term "heteroaromatic ring" as used herein is meant a 5-6 memberedring, containing 1-2 N-atoms, 1 S or O atom, or combination thereof, andincludes: pyridine, thiophene, furan, imidazole, 1,3-thiazole,1,3-oxazole, 1,2,3-thiadiazole, and the like. The limitation here beingthat the 1,2-disubstitution occurs on only ring carbons of theheteroaromatic ring. Preferred heteroaromatic rings are pyridine, furanand thiophene.

"Substituted phenyl" includes phenyl substituted by one or more of C₁-C₄ alkyl, C₁ -C₄ alkoxy, or halo, and the like, as defined above;representative examples include o, m-, p-methoxy phenyl;2,4-dimethoxyphenyl; 2-chloro-4-ethoxyphenyl; 3,5-dimethoxyphenyl;2,4-dichlorophenyl; 2-bromo-4-methylphenyl, o-fluorophenyl, and thelike.

"Haloalkyl" includes C₁ -C₄ alkyl, defined above, substitued with one ormore "halo" as defined above and inlcudes: trifluoromethyl,2,2-dichloroethyl and the like.

"C₁ -C₄ alkylthio" includes C₁ -C₄ alkyl, defined above, substitutedwith at least one divalent thio (--S--) grouping including; methylthio,ethylthio, isopropylthio, n-butylthio, and the like.

"C₁ -C₄ alkylsulfinyl" includes C₁ -C₄ alkyl, defined above, substitutedwith at least one --SO-- grouping including; methylsulfinyl,ethylsulfinyl; isopropylsulfinyl, and the like.

"C₁ -C₄ alkylsulfonyl" includes C₁ -C₄ alkyl, defined above, substitutedwith at least one sulfonyl group, --SO₂ --, including; methylsulfonyl,ethylsulfonyl, isopropylsulfonyl, n-butylsulfonyl, and the like.

"C₁ -C₄ mono or dialkyl amino" includes amino, substituted with one ormore C₁ -C₄ alkyl groups as defined hereinabove, including: methylamino,ethylamino, n-butylamino, t-butylamino, dimethylamino, diethylamino,methyl-t-butylamino, and the like.

The R group or groups on the benzene or heteroaromatic ring can bepresent initially in the process, e.g. phenyl, methyl, methoxy, cyanocarbomethoxy, trifluoromethyl, (as in the starting o-nitrophenol 1 inFlow Chart A) or added later by a conventional reaction, e.g. chloro, asby chlorination, nitro by nitration, or created from a starting or addedfunctional group present, e.g. converting a later added nitro group toan amino group by catalytic reduction, then alkylating to a mono ordialkylamine. An amino group can be subjected to diazotization to ahydroxy group, which can be followed by methylation to a methoxy group.Similarly, a hydroxy group can be converted to a thiol by the analogousprocedures described in J. Org. Chem. 31, pp 3980-3984 (1966) by Newmanand Karnes, and J. Org. Chem. 31, pp 410 (1966) by Kwart, H. and Evans,E. S. The resulting thiol can be alkylated to alkylthio, which can beoxidized to the corresponding sulfoxide or sulfone. Preferredsubstituents are H, C₁ -C₄ alkyl, C₁ -C₄ alkoxy and phenyl. Thesereactions and sequences are conventional in the art and it will beobvious to one skilled in the art to modify the benzene ring to arriveat an R radical disclosed herein.

By the term "pharmaceutically acceptable salts and esters thereof" ismeant, salts and esters of the acid groups in the final molecule whichcan be used as part of the human drug delivery system and include thesalts: sodium, potassium, calcium, ammonium, substituted ammonium,quaternary ammonium, and esters: ethyl ester, aceturate, besylate,edetate, phenpropionate, acetate, pamoate, and esters which serve as"prodrug" formulations which will hydrolyze in the body at physiologicalpH's to regenerate the acid, including pivaloylates, e.g. pivoxetil andpivoxil, and Kanebo esters, and the like. ##STR37## where y is 1-6,preferably 3, can contain at least one R' substituent as defined above,and can be alkyl, e.g., ##STR38## and the like.

An alkene bond can also be present in ##STR39## e.g., --CH₂--CH═CH;--CH₂ --CH═CH--CH₂ ; --CH₂ --CH₂ --CH═CH; --(CH₂)₃ --CH═CH, andthe like. ##STR40## where z is 6-20, preferably 8-14, can contain atleast one R" substituent as defined above, and can be alkyl; e.g.,##STR41## and the like.

An alkene bond can also be present in ##STR42## e.g., --CH₂--CH═CH--(CH₂)₈ --; --(CH₂)₈ --CH═CH--(CH₂)₂ --; --(CH₂)₉--CH═CH--(CH₂)₉ --; (CH₂)₄ --CH═CH--(CH₂)₄ --; and the like.

Preferred is where one R' or R" is H and particularly preferred is whereboth ##STR43## are alkyl.

Representative compounds of the instant invention within the abovegeneral formula are given by the following, structures; ##STR44##

Particularly preferred are the following compounds: ##STR45## where X isO or S and R, R', R", y and z are as defined above.

Preferred compounds within this class are: ##STR46## where X is O or S,and n is 8-14.

Also preferred compound are within these classes are: ##STR47## where nis 8-14. ##STR48## were n is 8-14.

The compounds of the instant invention can be made by the proceduresoutlined in the following Flowcharts. ##STR49##

As seen in Flow Chart A-2, o-nitrophenol 1, ethyl 4-bromobutyrate 2 andanhydrous K₂ CO₃ in e.g., dry acetone are heated at reflux or stirredfor an extended period of time at room temperature, under a nitrogenatmosphere to product ethyl 4-(2-nitrophenoxy) butyrate 3, in Step (A).

A solution of 3 in e.g., ethyl acetate is catalytically hydrogenated atroom temperature under e.g. 40 psig of H₂ in the presence of a 5% Pd/Ccatalyst to yield ethyl 4-(2-aminophenoxy)butyrate 4 in Step (B).

Step (C) comprises reacting diethyl dodecanoate 5 with barium hydroxideoctahydrate in methanol at ambient temperature to obtain the monomethylester 6.

In Step (D) the mono ester mono acid 6 is refluxed with thionyl chloridefor about 5 hours to produce the mono acid chloride, mono methyl ester7.

Step (E) comprises the reaction of the mono acid chloride 7 with theamine 4 at e.g., 0-10° C. in e.g., dry ether in the presence of ahydrogen acceptor e.g., triethylamine, to produce the amide 8.

In Step (F), the ether-amide diester 8 is de-esterified by e.g., 2.5 NNaOH in MeOH/H₂ O to yield after acidification the final product, diacid9.

Flow Chart B-2 illustrates the synthesis of the corresponding thiocompounds.

Step (G) illustrates the reaction of o-aminobenzenethiol with ethyl4-bromobutyrate which can be carried out in e.g., dry dimethoxyethane,under dry N₂, in the presence of a proton acceptor, e.g., dry powderedK₂ CO₃, to produce 11.

Step (H) illustrates the acylation of the amino group of 11 with ethyl11-bromoundecanoate in a dry solvent, e.g., dry ether, at 0° C. in thepresence of an acid acceptor, e.g., pyridine.

Step (I) illustrates the hydrolysis of the diester to the final diacid13, which can be accomplished with, e.g., NaOH/MeOH.

As seen in Flow Chart C-2, o-nitrophenol is benzylated under the sameconditions as in Step (A).

Step (K) shows the reduction of the nitro group using e.g., Raney Ni inethanol/NH₃ under 40 psig H₂.

Step (L) shows the trifluoroacetylation of 24 using e.g.,trifluoroacetic anhydride in dry ether and powdered dry sodiumcarbonate.

Step (M) shows the N-methylation which can be accomplished using, e.g.,methyl iodide in dry acetone and dry powdered KOH followed by removal ofthe N-trifluoroacetyl group with MeOH/H₂ O.

Step (N) shows the N-acylation of 27, using an acid chloride, e.g., 7,in e.g., dry methylene chloride and pyridine at 0° C.

Step (O) shows the debenzylation of 28, which can be accomplished bye.g., 10% Pd/C in MeOH under a H₂ atmosphere.

Step (P) shows the O-alkylation of 29 using e.g., ethyl 4-bromobutyrateand K₂ CO₃ in anhydrous acetone.

Step (Q) shows hydrolysis of the diester 30 to the diacid 31 byhydrolysis as e.g., described for Step (F).

Flow Chart D-2 shows the production of phosphonate type esters andacids.

Step (R) shows the condensation of 4 with 11-bromoundecanoic acid inanhydrous methylene chloride using N,N'-dicyclohexylcarbodiimide and4-dimethylaminopyridine to produce the important bromo intermediate 32.

Step (S) shows the reaction of 32 with triethylphosphite at e.g., 180°C. under N₂ to produce the phosphonate ester 33.

Step (T) converts 33 via bromotrimethylsilane to the monoacid 34.

Step (U) uses the similar hydrolysis conditions of Step (F) to producethe phosphoniccarboxylic diacid 35.

The corresponding phosphinic acids can be analogously made from 32 byknown procedures in the art.

Flow Chart E-2 illustrates the synthesis of the sulfonic acid types ofthe invention compounds.

Step (V) shows reaction of the intermediate 32 with thiourea in EtOH/H₂O under N₂ at 90° C. to yield the isothiouronium salt 36.

Step (W) shows the reaction of 32 with sodium thiosulfate under theconditions of Step (V) to yield the thiosulfate ester 37.

Further oxidation of esters 36 or 37 via the Showell or Zieglerprocedures described in Step W in the examples yields the correspondingsulfonic acid 38.

The corresponding sulfinic acid can be prepared from 36 by the procedureof J. M. Sprague and T. B. Johnson, JACS 59, 2440 (1937).

The corresponding sulfonamide can be produced from the sulfonic acid 38,by protecting, e.g., the carboxylic acid via an ester, converting thesulfonic acid to a sulfonyl chloride, treating the sulfonyl chloridewith ammonia and then hydrolyzing the protected carboxylic ester to thecorresponding acid.

Flow Chart F-2 shows the corresponding synthesis of the pyridine analogsof 8 and 9.

In Step (X), the nitrohydroxy pyridine is O-alkylated first usingconditions analogous to Step (A) to produce 40.

Step (Y) shows reducing the nitro group in the same manner as describedfor Step (B).

Step (Z) shows acylating the amino group in the same manner as describedfor 8 in Step (E) to produce the diester 42. Hydrolysis produces thediacid 43.

Flow Chart G-2 shows the production of some amides 46 of the invention.

In Step (AA), o-aminophenol is reacted directly with 7 under theconditions of Step (E) to produce the N-acylated phenol 44.

In Step (BB), O-alkylation of 44 as carried out using4-bromobutyronitrile under conditions similar to Step (A), produces 45.

Step (CC) shows the hydrolysis of the nitrile to the amide 46 using MnO₂in methylene chloride.

Flow Chart H-2 illustrates an alternate route to 9 by starting witho-aminophenol, acylating to produce 44, then reacting 44 under theconditions of Step (A) to produce 8, then hydrolysis using Step (F) toyield 9.

Thus, by using the above described methods in the Flow Charts and thereaction starting materials and reagents described herein, all of thecompounds described and encompassed by the claim can be synthesized byone skilled in the art.

It is obvious that other nitrophenols can be substituted for 1 in FlowCharts A-2 and C-2 to provide the scope of the compounds covered by thisinvention and include the following:

2-nitrophenol

2-nitro-6-methylphenol

2-nitro-5-methylphenol

2-nitro-4-methylphenol

2-nitro-3-methylphenol

2-nitro-4-phenylphenol

2-nitro-5-phenylphenol

2-nitro-4-chlorophenol

2-nitro-4-fluorophenol

2-nitro-4-trifluoromethylphenol

2-nitro-4-hydroxyphenol

2-nitro-4-methoxyphenol

2-nitro-6-ethoxyphenol

2-nitro-4-methylthio-phenol

2-nitro-4-methylsulfinylphenol

2-nitro-4-methylsulfonylphenol

4-nitro-3-hydroxypyridine

3-nitro-4-hydroxy-5-methylpyridine

3-nitro-4-hydroxy-6-methylpyridine

2-methyl-3-nitro-4-hydroxypyridine

2-hydroxy-3-nitro-5-phenylpyridine

2-nitro-3-hydroxy-5-phenylpyridine

2-hydroxy-3-nitro-5-chloropyridine

2-nitro-3-hydroxy-5-trifluoromethylpyridine

2-methoxy-4-nitro-5-hydroxypyridine

3-nitro-4-hydroxy-5-ethoxypyridine

2-methylthio-4-nitro-5-hydroxypyridine

2-nitro-3-hydroxy-thiophene

3-nitro-4-hydroxy-thiophene

3-hydroxy-2-nitro-5-methyl-thiophene

3-hydroxy-2-nitro-4-methyl-thiophene

2-hydroxy-3-nitro-5-phenyl-thiophene

2-nitro-3-hydroxy-4-phenyl-thiophene

2-hydroxy-3-nitro-4-chlorothiophene

2-hydroxy-3-nitro-4-fluorothiophene

and the like.

It is obvious that suitable replacement compounds for 2 with other haloalkyl esters, known in the art, and that suitable replacement of 6 withother diesters, available in the art, will yield all of the ether-amidederivatives within the scope of the claims.

Representative examples of 2 useful in the invention process include,but are not limited to:

Br--CH₂ --COOMe,

Cl--CH₂ CH₂ CH₂ COOCH(CH₃)₃,

Br--CH₂ CH₂ CH₂ CH₂ COOMe,

Br--CH₂ CH₂ CH₂ CH₂ CH₂ COOEt,

Br--CH₂ CH₂ CH₂ CH₂ CH₂ CH₂ COOCH₂ CH₂ CH₂ CH₃,

Br--CH₂ CH(CH₃)COOMe,

Br--CH₂ CH(CH₃)CH₂ COOEt,

Br--CH₂ CH₂ CH₂ COOMe,

Br--CH₂ CH(OCH₃)CH₂ COOCH(CH₃)₂,

Cl--CH₂ CH(OCH₂ CH₃)CH₂ COOMe,

Br--CH₂ CH(F)CH₂ COOMe,

and the like.

Representative examples of other compounds substitutable for 6 anduseful in the invention are:

HOOC(CH₂)₆ COOMe,

HOOC(CH₂)₇ COOMe,

HOOC(CH₂)₈ COOMe,

HOOC(CH₂)₉ COOMe,

HOOC(CH₂)₁₀ COOMe,

HOOC(CH₂)₁₁ COOMe,

HOOC(CH₂)₁₂ COOEt,

HOOC(CH₂)₁₃ COOCH(CH₃)₂,

HOOC(CH₂)₁₄ COOCHCH₂ CH₃,

HOOC(CH₂)₁₅ COO(CH₂)₃ CH₃,

HOOC(CH₂)₁₆ COOCH₃,

HOOC(CH₂)₁₇ COOCH₃,

HOOC(CH₂)₁₈ COOMe,

HOOC(CH₂)₁₉ COOEt,

HOOC(CH₂)₂₀ COOPh,

HOOC(CH₂)₁₀ COOCH₂ Ph,

HOOCCH(CH₃)--(CH₂)₁₀ COOMe,

HOOC--CH₂ CH--(CH₃)(CH₂)₁₀ COOMe,

HOOC--CH₂ CH₃ CH(CH₃)CH₂ COOEt, ##STR50## HOOC--CH₂ CH(OCH₃)(CH₂)₇COOCH(CH₃)₂, where Ph is phenyl,

and the like.

Representative examples of compounds produced by this process includethose in the following list.

The nomenclature used herein for the acid radicals is:

P(O)(OH)₂, phosphono;

--COOH, carboxy;

--CONH₂, aminocarbonyl;

--SO₃ H, sulfo;

--SO₂ H, sulfino;

--SSO₃ H, thiosulfato, as the sodium salt.

4-(2-(20-Carboxyeicosanoylamino)phenoxy)butyric acid;

4-(2-(19-Carboxynonadecanoylamino)phenoxy)butyric acid;

4-(2-(18-Carboxyoctadecanoylamino)phenoxy)butyric acid;

4-(2-(17-Carboxyheptadecanoylamino)phenoxy)butyric acid;

4-(2-(16-Carboxyhexadecanoyl-N-methylamino)phenoxy)-butyric acid;

4-(2-(15-Carboxypentadecanoylamino)phenoxy)butyramide;

4-(2-(14-Carboxytetradecanoylamino)phenoxy)butyric acid;

4-(2-(13-Carboxyl-tridecanoylamino)phenoxy)butyric acid;

4-(2-(12-Carboxy-dodecanoylamino)phenoxy)butyric acid;

4-(2-(11-Carboxy-undecanoylamino)phenoxy)butyric acid;

4-(2-(10-Carboxy-decanoylamino)phenoxy)butyric acid;

4-(2-(9-Carboxy-nonanoylamino)phenoxy)butyric acid;

4-(2-(8-Carboxyoctanoylamino)phenoxy)butyric acid;

4-(2-(7-Carboxyheptanoylamino)phenoxy)butyric acid;

4-(2-(6-Carboxyhexanoylamino)butyric acid;

4-(2-(20-Carboxyeicosanoylamino)phenylthio)butyric acid;

4-(2-(19-Carboxynonadecanoylamino)phenylthio)butyric acid;

4-(2-(18-Carboxyoctadecanoylamino)phenylthio)butyric acid;

4-(2-(17-Carboxyheptadecanoyl-N-ethylamino)phenylthio)butyric acid;

4-(2-(16-Carboxyhexadecanoylamino)phenylthio)butyric acid;

4-(2-(15-Carboxypentadecanoylamino)phenylthio)butyric acid;

4-(2-(14-Carboxytetradecanoylamino)phenylthio)butyramide;

4-(2-(13-Carboxytridecanoylamino)phenylthio acid;

4-(2-(12-Carboxy-dodecanoylamino)phenylthio)butyric acid;

4-(2-(11-Carboxy-undecanoylamino)phenylthio)butyric acid;

4-(2-(10-Carboxydecanoylamino)phenylthio)butyric acid;

4-(2-(9-Carboxynonanoylamino)phenylthio)butyric acid;

4-(2-(8-Carboxyoctanoylamino)phenylthio)butyric acid;

4-(2-(7-Carboxyheptanoylamino)phenylthio)butyric acid;

4-(2-(6-Carboxyhexanoylamino)phenylthio)butyric acid;

3-(2-(16-Carboxyhexadecanoylamino)phenoxy)propionic acid;

4-(2-(15-Carboxyisohexadecanoylamino)phenoxy)butyric acid;

4-(2-(14-Carboxytetradecanoylamino)phenoxy)butyric acid;

5-(2-(13-Carboxytridecanoylamino)phenoxy)valeric acid;

5-(2-(12-Carboxydodecanoylamino)phenoxy)valeric acid;

5-(2-(11-Carboxyisododecanoylamino)valeric acid;

4-(2-(11-Carboxyundecanoylamino)isovaleric acid;

4-(2-(10-Carboxydecanoylamino)isovaleric acid;

5-(2-(9-Carboxynonanoylamino)phenoxy)valeric acid;

6-(2-(9-Carboxynpnanoylamino)phenoxy)caproic acid;

6-(2-(8-Carboxyoctanoylamino)phenoxy)caproic acid;

6-(2-(7-Carboxyisooctanoylamino)phenoxy)caproic acid;

7-(2-(7-Carboxyheptanoylamino)phenoxy)enanthic acid;

7-(2-(6-Carboxyhexanoylamino)phenoxy)enanthic acid;

7-(2-(5-Carboxyisohexanoylamino)phenoxy)enanthic acid;

2-(2-(12-Carboxydodecanoylamino)phenoxy)acetic acid;

2-(2-(11-Carboxyundecanoylamino)phenoxy)acetic acid;

2-(2-(10-Carboxydecanoylamino)phenoxy)acetic acid;

3-(2-(9-Carboxynonanoylamino)phenoxy)propionic acid;

3-(2-(12-Carboxydodecanoylamino)phenylthio)propionic acid;

3-(2-(11-Carboxyundecanoylamino)phenylthio)propionic acid;

3-(2-(11-Carboxyundecanoylamino)phenylthio)isobutyric acid;

4-(2-(19-Carboxynonadecanoyl-N-methylamino)phenylthio)butanesulfonicacid;

4-(2-(18-Carboxyoctadecanoylamino)phenylthio)butanesulfonic acid;

4-(2-(17-Carboxyheptadecanoylamino)phenylthio)butanesulfinic acid;

4-(2-(16-Carboxyhexadecanoylamino)phenylthio)butanethiosulfonic acid,sodium salt;

4-(2-(14-Carboxytetradecanoyl N-propylamino)phenylthio)butanephosphonicacid;

4-(2-(13-Carboxytridecanoylamino)phenylthio)butanesulfonic acid;

4-(2-(12-Carboxydodecanoylamino)phenylthio)butanesulfinic acid;

4-(2-(11-Carboxyundecanoylamino)phenylthio)butanethiosulfonic acid,sodium salt;

4-(2-(9-Carboxynonanoylamino)phenylthio)butanephosphonic acid;

4-(2-(8-Carboxyoctanoylamino)phenylthio)butanesulfonic acid;

4-(2-(7-Carboxyheptanoylamino)phenylthio)butanesulfinic acid;

4-(2-(6-Carboxyhexanoylamino)phenylthio)butanethiosulfonic acid, sodiumsalt;

3-(2-(15-Carboxyisohexadecanoylamino)phenoxy)isobutanephosphonic acid;

3-(2-(14-Carboxytetradecanoylamino)phenoxy)isobutanoic acid;

5-(2-(13-Carboxytridecanoylamino)phenoxy)pentanesulfinic acid;

5-(2-(12-Phosphonododecanoylamino)phenoxy)valeramide;

5-(2-(11-Sulfoundecanoylamino)valeric acid;

5-(2-(10-Sulfinodecanoyl N-methylamino)phenoxy valeric acid;

5-(2-(9-Thiosulfatononanoylamino)phenoxy)valeric acid, sodium salt;

6-(2-(9-Phosphonononanoylamino)phenoxy)caproic acid;

6-(2-(7-Sulfoisooctanoyl-N-methylamino)phenoxy)caproic acid;

7-(2-(7-Sulfinoheptanoyl-N-ethylamino)phenoxy)enanthic acid;

7-(2-(6-Thiosulfatohexanoylamino)phenoxy)enanthamide, sodium salt

7-(2-(5-Phosphonoisohexanoylamino)phenoxy)enanthic acid;

2-(2-(11-Sulfoundecanoylamino)phenoxy)acetic acid;

2-(2-(10-Sulfodecanoyl-N-propylamino)phenoxy)acetic acid;

3-(2-(9-Sulfinononanoylamino)phenoxy)propionic acid;

3-(2-(12-Thiosulfatododecanoylamino)phenylthio)propionamide, sodiumsalt;

3-(2-(11-Phosphonoundecanoylamino)phenylthio)propionic acid;

3-(2-(11-Sulfoundecanoylamino)-4-methyl-phenylthio)isobutyric acid;

3-(2-(12-Sulfinododecanoylamino)phenylthio)isobutyramide;

5-(2-(11-Thiosulfoundecanoyl-N-butylamino)phenylthio)valeric acid,sodium salt;

5-(2-(10-Phosphonodecanoylamino)phenylthio)valeric acid;

5-(2-(12-Phosphonododecanoylamino)phenylthio)pentane-sulfonic acid;

5-(2-(11-Carboxydecanoylamino)phenylthio)pentane sulfinic acid;

5-(2-(10-Phosphonodecanoylamino)phenylthio)pentanethiosulfonic acid;

6-(2-(12-Phosphonododecanoylamino)phenylthio)hexanephosphonic acid;

4-(2-(11-Sulfinoundecanoylamino)4-methyl-phenoxy)butane-thiosulfonicacid, sodium salt;

4-(2-(12-Sulfododecanoylamino)6-methylphenoxy)butane sulfonic acid;

4-(2-(11-Sulfodecanoylamino)3-chloro)phenylthio)-butane-sulfinic acid;

4-(2-(10-Sulfodecanoylamino)4-methylphenoxy)butanethiosulfonic acid,sodium salt;

4-(2-(12-Sulfododecanoylamino)6-methylphenoxy)-butane-phosphonic acid;

5-(2-(11-Sulfinoundecanoylamino)-3-methylphenylthio)pentane-sulfonicacid;

4-(2-(11-Sulfinoundecanoylamino)-3-methylsulfonylphenoxy)butane-sulfinicacid;

4-(2-(11-Sulfinoundecanoylamino)-4-methylsulfonyl)-phenylthio)butanesulfonicacid;

4-(2-(12-Sulfinododecanoylamino)5-ethyl-phenoxy)-butane-phosphonic acid;

4-(2-(10-Sulfinodecanoylamino)-3,5-dimethylphenoxy)-butane-sulfonicacid;

4-(2-(9-Thiosulfatononanoylamino)-4-fluoro-phenoxy)butane-sulfinic acid,sodium salt;

4-(2-(12-Thiosulfatododecanoylamino)-5-trifluromethylphenoxy)butane-thiosulfonicacid, sodium salt;

4-(2-(10-Thiosulfatodecanoylamino)-4-hydroxyphenylthio)butane-phosphbnicacid, sodium salt;

4-(2-(9-Phosphonononanoylamino)-3,5-dimethoxyphenylthio)butyric acid;

5-(2-(11-Sulfoundecanoylamino)-4-nitrophenoxy)-valeric acid;

4-(2-(11-Sulfinoundecanoylamino)-5-amino-3-methylphenoxy)butyric acid;

4-(2-(11-Thiosulfatoundecanoylamino)-5-amino-4-methylphenylthio)butyricacid, sodium salt;

4-(2-(12-Phosphonododecanoylamino)-4-dimethyl-aminophenoxy)butyric acid;

4-(2-(10-Sulfodecanoylamino)-phenoxy)butyric acid;

3-(2-(9-Sulfinononanoylamino)phenoxy)propionic acid;

3-(2-(12-Thiosulfatododecanoylamino)phenoxy)-3-methylpropionic acid,sodium salt;

3-(2-(11-Phosphonodecanoylamino)thienyloxy)-2-chloropropionic acid;

4-(2-(9-Sulfononanoylamino)thienyloxy-3-ethoxybutyric acid;

4-(2-(12-Sulfinododecanoylamino)phenoxy)-2-fluorobutyric acid;

7-(2-(11-Thiosulfatoundecanoylamino)phenoxy)6-aminoenanthic acid, sodiumsalt;

5-(2-(11-Phosphonoundecanoylamino)-3-methylphenoxy)-4-oxo-valeric acid;

4-(2-(12-Sulfododecanoylamino)phenoxy)but-2-enoic acid;

4-(2-(11-Sulfinodecanoylamino)phenoxy)but-2-enoic acid;

4-(2-(10-Thiosulfatodecanoylamino)phenoxy)-4-methylene valeric acid,sodium salt;

4-(2-(9-Phosphonononanoylamino)phenoxy)-4-fluoro-2-butenoic acid;

4-(2-(11-Sulfo-3-methylbutanoylamino)thienyloxy)-butyric acid;

4-(2-(4-Sulfino-3-chlorobutanoylamino)thienyloxy)-butyric acid;

4-(2-(9-Thiosulfato-2-methoxynonanoylamino)thienyloxy)butyric acid,sodium salt;

4-(2-(4-Phosphono-2-ethoxybutanoylamino)phenoxy)butyric acid;

4-(2-(14-Sulfo-14-fluoro-2-acetamidotetradecanoylamino)-3-methylphenoxy)butyricacid;

4-(2-13-Sulfino-2-oxotridecanoylamino)-4-methylthio)-phenyloxy)butyricacid;

4-(2-(12-Thiosulfatododecanoyl-3-en-amino)phenoxy)butyric acid;

4-(2-(11-Phosphonoundecanoyl-7-ene-amino)phenoxy)butyric acid;

4-(2-(4-Sulfo-2-fluoro-2-butenoylamino)phenoxy)-butyric acid;

4-(2-(12-Sulfinododecanoylamino)-4-methyl-3-pyridyloxy)butyric acid;

4-(2-(11-Thiosulfatoundecanoylamino)-4-methyl-3-pyridyloxy)butyric acid;

4-(2-(10-Phosphonodecanoylamino)-5-methyl-3-pyridyloxy)butyric acid;

4-(2-(11-Sulfinodecanoylamino)-4-nitro-3-pyridylthiobutyric acid;

4-(2-(10-Thiosulfatodecanoylamino)-6-methylsulfonyl-3-pyridyloxy)butyricacid, sodium salt;

4-(2-(9-Phosphonononanoylamino)5-chloro-3-pyridylthio)butyric acid;

4-(2-(11-Sulfoundecanoylamino)5-methylsulfonyl-3-pyridylthio)butyricacid;

4-(2-(11-Sulfinoundecanoylamino)-6-methyl-3-pyridylthio)butyric acid;

4-(2-(11-Thiosulfatoundecanoylamino)-4,6-dimethyl-3-pyridyloxy)butyricacid, sodium salt;

4-(2-(12-Phosphonododecanoylamino)-5-(methylthio)-3-pyridyloxy)butyricacid;

4-(2-(10-Sulfodecanoylamino)-5-methoxy-3-pyridyloxy)butyric acid;

4-(2-(9-Sulfinononanoylamino)-4-fluoro-6-methyl-3-pyridyloxy)butyricacid;

4-(2-(12-Thiosulfatododecanoylamino)5-(methylamino)-3-pyridyloxy)butyricacid, sodium salt;

4-(2-(11-Phosphonoundecanoylamino)4-phenyl-3-pyridylthio)butyric acid;

4-(2-(9-Sulfounonanoylamino)6-methoxy-3-pyridylthio)butyric acid;

4-(2-(12-Sulfinododecanoylamino)-6-trifluoromethyl-3-pyridyloxy)butyricacid;

5-(2-(11-Thiosulfatoundecanoylamino)-4-methyl-3-thiophenyloxy)valericacid, sodium salt;

4-(2-(11-Phosphonoundecanoylamino)-4-methyl-3-thiophenyloxy)butyricacid;

4-(2-(12-Sulfododecanoylamino)-5-methyl-3-thiophenylthio)butyric acid;

4-2(-(11-Sulfinoundecanoylamino)-4-methyl-3-thiophenylthio)butyric acid;

4-(2-(10-Thiosulfatodecanoylamino)-5-methyl-3-thienylthio)butyric acid,sodium salt;

4-(2-(9-Phosphonononanoylamino)-4-hydroxy-3-thienyloxy)butyric acid:

4-(2-(11-Sulfodecanoylamino)-4-methylthio-3-thienyloxy)butyric acid;

4-(2-(10-Sulfinodecanoylamino)-4-methylsulfonyl-3-thienyloxy)butyricacid;

4-(2-(9-Thiosulfatononanoylamino)-4-methylsulfonyl-3-thienyloxy)butryicacid, sodium salt;

4-(2-(12-Phosphonododecanoylamino)-5-trifluoromethyl-3-thienyloxy)butyricacid;

4-(2-(11-Sulfoundecanoylamino)-4-methyl-5-phenyl-3-thienyloxy)butyricacid;

4-(2-(11-Sulfinoundecanoylamino)-5-methylamino-3-thienyloxy)butyricacid;

4-(2-(12-Thiosulfatododecanoylamino)-5-dimethylamino-3-thienyloxy)butyricacid, sodium salt;

4-(2-(11-Phosphonoundecanoylamino)-4-amino-3-thienyloxy)butyric acid;

Preferred compounds in the invention include:

4-(2-(11-Carboxyundecanoylamino)phenoxy)butyric acid,

4-(2-(11-Carboxyundecanoylamino)phenylthio)butyric acid,

4-(2-(9-Carboxynonanoylamino)phenoxy)butyric acid,

4-(2-(10-Carboxydecanoylamino)phenoxy)butyric acid,

4-(2-(12-Carboxydodecanoylamino)phenoxy)butyric acid,

4-(2-(13-Carboxytridecanoylamino)phenoxy)butyric acid,

4-(2-(15-Carboxypentadecanoylamino)phenoxy)butyric acid,

4-(2-(11-Carboxyundecanoylamino)-4-methylphenoxy)-butyric acid,

4-(2-(11-Carboxyundecanoylamino)-5-methylphenoxy)-butyric acid.

Also included as a 5α-reductase inhibitor in this invention is an agentof the following formula: ##STR51## wherein A is an 1,2-disubstitutedaromatic ring, preferably a benzene ring;

D is OH, NH₂, NHR_(c), OR_(c) ;

X is O, S, SO, or SO₂ ;

R is H,

C₁ -C₄ alkyl,

phenyl or substituted phenyl,

halo,

haloalkyl,

hydroxy,

carboxy,

cyano,

C₁ -C₄ alkoxy,

C₁ -C₄ alkylthio,

C₁ -C₄ alkylsulfinyl,

C₁ -C₄ alkylsulfonyl,

nitro,

amino,

C₁ -C₄ mono or di-alkylamino;

R' and R" are independently

H,

halo,

C₁ -C₄ alkyl or C₁ -C₄ alkoxy,

amino, or oxo, where CH--R' or CH--R" in the formula become --C═O;

R_(a) is H, C₁ -C₄ alkyl;

R_(b), R_(c) are independently, C₁ -C₁₂ alkyl, phenyl,

phenyl-C₁ -C₄ alkyl;

n is 0-2;

y is 1-6;

z is 6-20; and

wherein ##STR52## can independently represent substituted orunsubstituted alkyl radicals or alkenyl radicals containing at least onealkene bond;

and pharmaceutically acceptable salts and esters thereof.

The compounds of the instant invention are inhibitors of the humantestosterone 5α-reductase.

The scope of the compounds of the instant invention are described by theabove-described formula.

In the description of the formula the following terms are used which arehereby defined:

X can be O or S, preferably one X being O, and particularly preferredwherein both Xs are O, i.e., the catechol structure.

"C₁ -C₄ alkyl" includes linear or branched species, e.g. methyl, ethyl,n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, t-butyl;and "C₁ -C₁₂ alkyl" includes alkyl up to 12 carbons including n-octyl,t-decyl, n-dodecyl.

"Phenyl C1-C4 alkyl" includes benzyl, 2-phenethyl, and the like;

"C₁ -C₄ alkoxy" includes linear or branched species, e.g., methoxy,ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy,t-butoxy;

"Halo" includes fluoro, chloro, bromo or iodo;

"Substituted phenyl" includes phenyl substituted by one or more of C₁-C₄ alkyl, C₁ -C₄ alkoxy, or halo, and the like, as defined above;representative examples include o, m-, p-methoxy phenyl;2,4-dimethoxyphenyl; 2-chloro-4-ethoxyphenyl; 3,5-dimethoxyphenyl;2,4-dichlorophenyl; 2-bromo-4-methylphenyl, o-fluorophenyl, and thelike.

"Haloalkyl" includes C₁ -C₄ alkyl, defined above, substituted with oneor more "halo" as defined above and includes: trifluoromethyl,2,2-dichloroethyl and the like.

"C₁ -C₄ alkylthio" includes C₁ -C₄ alkyl, defined above, substitutedwith at least one divalent thio (--S--) grouping including; methylthio,ethylthio, isopropylthio, n-butylthio, and the like.

"C₁ -C₄ alkylsulfinyl" includes C₁ -C₄ alkyl, defined above, substitutedwith at least one --SO-- grouping including; methylsulfinyl,ethylsulfinyl; isopropylsulfinyl, and the like.

"C₁ -C₄ alkylsulfonyl" includes C₁ -C₄ alkyl, defined above, substitutedwith at least one sulfonyl group, --SO₂ --, including; methylsulfonyl,ethylsulfonyl, isopropylsulfonyl, n-butylsulfonyl, and the like;

"C₁ -C₄ mono or dialkyl amino" includes amino, substituted with one ormore C₁ -C₄ alkyl groups as defined hereinabove, including: methylamino,ethylamino, n-butylamino, t-butylamino, dimethylamino, N,N-diethylamino,methyl-t-butylamino, and the like.

The R group or groups on the benzene ring can be present initially inthe process, e.g. phenyl, methyl, methoxy, cyano, carbomethoxy,trifluoromethyl, (present as in the starting 6-nitrophenol 1 in FlowChart A) or added later by a conventional reaction, e.g. chloro, as bychlorination, nitro by nitration, or created from a starting or addedfunctional group present, e.g. converting a later added nitro to anamino group by catalytic reduction, then alkylating to a mono ordialkylamine. An amino group can be subjected to diazotization to ahydroxy group, which can be followed by methylation to a methoxy group.Similarly, a hydroxy group can be converted to a thiol by the analogousprocedures described in J. Org. Chem. 31, pp 3980-3984 (1966) by Newmanand Karnes, and J. Org. Chem. 31, pp 410 (1966) by Kwart, H. and Evans,E. S. The resulting thiol can be alkylated to alkylthio, which can beoxidized to the corresponding sulfoxide or sulfone. Preferredsubstituents are H, C₁ -C₄ alkyl, C₁ -C₄ alkoxy and phenyl. Thesereactions and sequences are conventional in the art and it will beobvious to one skilled in the art to modify the benzene ring to arriveat an R radical disclosed herein.

By the term "pharmaceutically acceptable salts and esters thereof" ismeant salts and esters of the acid groups in the final molecule whichcan be used as part of the human drug delivery system and include thesalts: sodium, potassium, calcium, ammonium, substituted Ammonium,quaternary ammonium, and esters: ethyl ester, aceturate, besylate,edetate, phenpropionate, acetate, pamoate, and esters which serve as"prodrug" formulations which will hydrolyze in the body at physiologicalpH's to regenerate the acid, including pivaloylates, e.g. pivoxetil andpivoxil, and Kanebo esters, and the like. ##STR53## where y is 1-6,preferably 3, can contain at least one R' substituent as defined above,and can be, e.g., ##STR54## and the like.

An alkene bond can also be present in ##STR55## e.g., CH₂ --CH═CH--; CH₂--CH═CH--CH₂ --; --CH₂ --CH═CH--; --(CH₂)₃ --CH═CH-- and the like.##STR56## where z is 6-20, preferably 8-14, can contain at least one R"substituent as defined above, and can be completely alkyl; e.g.,(CH₂)n-COOH, where n is 8-14 preferably and the like.

An alkene bond can also be present in ##STR57## e.g., --(CH₂)₄--CH═CH--(CH₂)₄ --, and the like.

Preferred is where one R' or R" is H and particularly preferred is whereboth ##STR58## are alkyl.

Preferred compounds of the instant invention are given by the followingformulas; ##STR59## wherein R, R', R", Y, Z, R_(b) are defined above;and particularly preferred are: ##STR60## where n is 8-14, and R_(b) ismethyl, ethyl, cyclopropyl, isopropyl, n-propyl, t-butyl, phenyl orbenzyl.

The compounds of the instant invention can be made by the proceduresoutlined in the following Flowcharts. ##STR61##

As seen in Flow Chart A-3, o-nitrophenol 1, ethyl 4-bromobutyrate 2 andanhydrous K₂ CO₃ in e.g., dry acetone are heated at reflux e.g. for12-100 hours, or stirred for an extended period of time at roomtemperature, under a nitrogen atmosphere to product ethyl4-(2-nitrophenoxy) butyrate 3, in Step (A).

A solution of 3 in e.g., ethyl acetate is catalytically hydrogenated atroom temperature under e.g. 40 psig of H₂ in the presence of a 5% Pd/Ccatalyst to yield ethyl 4-(2-aminophenoxy)butyrate 4 in Step (B).

Step (C) comprises reacting the 12-bromo dodecanoic acid 5 withisopropyl mercaptan in a suitable solvent, e.g., dimethoxyethane, atabout 80-85° C. to obtain the acid 6.

In Step (D) the mono acid 6 is reacted with the amine 4 andN'N'-dicyclohexylcarbodiimide (DCC) at e.g., room temperature in e.g.,dry methylene chloride, optionally in the presence of4-dimethylaminopyridine, to produce the amide 7.

In Step (E), the ether-amide 7 is de-esterified by e.g., 2.5 N NaOH inMeOH/H₂ O to yield the final product, monoacid 8.

The monoacid 8 can be treated with NaIO₄ in (acetone/water) at roomtemperature for (4-24 hours) to produce the corresponding sulfoxide 8a.Additionally, 8 can be treated with meta-chlorobenzoic acid in (CH₂ Cl₂)at a temperature of about 0° to 25° C. for (1-24 hours) to produce thecorresponding sulfone 8b.

In Step (F) the ester 7 is treated with ammonia in (methanol) at roomtemperature for, e.g., 1-7 days to produce the amide 9.

Flow Chart B-3 illustrates the synthesis of the sulfur analogs of theinvention compounds.

In Step G, the orthoaminothiophenol is reacted with the bromoester 2under conditions similar to Step A to produce the thioether 11.

In Step (H), the thiother 11 is reacted with an alkylthioalkanoic acidunder similar conditions using DCC analogously as in Step D to producethe acylated ester 12.

In Step I, the ester 12 is hydrolyzed to produce the free thio acid 13,which has the 5-α-reductase activity described herein.

As seen in Flow Chart C-3, the compound 13 can further be oxidized tothe sulfoxide in Step J_(a), starting with the thio compound 14 toproduce the sulfoxide 15, which can be hydrolyzed, analogous to theconditions in Step I to produce the active acid 16.

In a similar manner, 14 can be converted to the sulfone-ester 17, whichcan then be hydrolyzed analogous to the conditions in Step I to thecorresponding acid 18.

Alternatively, the sulfur in o-nitrobenzene thiol as a separate startingmaterial analogous to 1, can be coupled to yield the ester alkylthiocompound corresponding to 3 which can be oxidized to the correspondingsulfoxide or sulfone, then followed by reduction of the nitro group tothe amino and then coupled with a suitable reagent e.g., 6, to yield thelinear amide containing unoxidized sulfur analogous to 7. A furthermodification is where the sulfuracylating agent is first oxidized to thecorresponding sulfoxide or sulfone, then coupled with the amino group ofe.g., 11 to yield e.g. 13 containing only an oxidized sulfur in theamide chain.

It is obvious that other nitrophenols can be substituted for 1 in FlowChart A-3 to provide the scope of the compounds covered by thisinvention and include the following:

2-nitrophenol

2-nitro-6-methylphenol

2-nitro-5-methylphenol

2-nitro-4-methylphenol

2-nitro-3-methylphenol

2-nitro-4-phenylphenol

2-nitro-5-phenylphenol

2-nitro-4-chlorophenol

2-nitro-4-(trifluoromethyl)phenol

2-nitro-4-methoxyphenol

2-nitro-6-ethoxyphenol, and the like.

Starting materials for Flow Charts B-3 and C-3 in addition to 10 arecommercially available and readily made by prior art procedures andinclude all of the above listed compounds where --SH is substituted for--OH, ortho to the nitro group.

Other starting materials for 2 in both Flow Charts A-3 and B-3 includethe following:

Br--CH₂ --COOMe,

Cl--CH₂ CH₂ CH₂ COOCH(CH₃)₃,

Br--CH₂ CH₂ CH₂ CH₂ COOMe,

Br--CH₂ CH₂ CH₂ CH₂ CH₂ COOEt,

Br--CH₂ CH₂ CH₂ CH₂ CH₂ CH₂ COOCH₂ CH₂ CH₂ CH₃,

Br--CH₂ CH(CH₃)COOMe,

Br--CH₂ CH(CH₃)CH₂ COOEt,

Br--CH₂ CH₂ CH₂ COOMe,

Br--CH₂ CH(OCH₃)CH₂ COOCH(CH₃)₂,

Cl--CH₂ CH(OCH₂ CH₃)CH₂ COOMe,

Br--CH₂ CH(F)CH₂ COOMe,

and the like.

Other starting materials for the acid 6 to produce the acid foracylating the amino group in 4 or 11 include the following:

MeS--(CH₂)₆ COOH,

MeS--(CH₂)₇ COOH,

(CH₃)₂ CHS--(CH₂)₈ COOH,

EtS--(CH₂)₉ COOH,

CH₃ CH₂ CH₂ S(CH₂)₁₀ COOH,

(CH₃)₂ CHS(CH₂)₁₁ COOH,

MeS--(CH₂)₁₂ COOH,

EtS--(CH₂)₁₃ COOH,

CH₃ CH₂ CH₂ S--(CH₂)₁₄ COOH,

(CH₃)₂ CHS--(CH₂)₁₅ COOH,

CH₃ (CH₂)₃ S--(CH₂)₁₆ COOH,

(CH₃)₂ CH--CH₂ S--(CH₂)₁₇ COOH,

CH₃ --CH₂ --CH₂ --S--(CH₂)₁₈ COOH,

(CH₃)₂ CHS--(CH₂)₁₉ COOH,

EtS--(CH₂)₂₀ COOH,

MeS--CH(CH₃)--(CH₂)₁₀ COOH,

(CH₃)₂ CHS--CH₂ CH₂ CH(CH₃)CH₂ COOH, ##STR62## EtS--CH₂ CH(OCH₃)(CH₂)₇COOH, CH₃ CH₂ CH₂ S--CH₂ CH(OCH₂ CH₃)CH₂ CH₂ COOH,

CH₃ (CH₂)₇ --S--CH₂ --COOH

(CH₃)₂ CH(CH₂)₅ --S--CH₂ --COOH

CH₃ (CH₂)₉ --S--CH₂ --COOH

CH₃ (CH₂)₁₁ S--CH₂ COOH, and the like.

Representative compounds of the instant invention include, but are notlimited to:

4-(2-(20-Isopropylthioeicosanoylamino)phenoxy)butyric acid;

4-(2-(19-Methylthiononadecanoylamino)phenoxy)butyric acid;

4-(2-(18-Ethylthioloctadecanoylamino)phenoxy)butyric acid;

4-(2-(17-Isopropylthioheptadecanoylamino)phenoxy)-butyric acid;

4-(2-(16-Methylthiohexadecanoylamino)phenoxy)butyric acid;

4-(2-(15-Methylsulfinylpentadecanoylamino)phenoxy)-butyric acid;

4-(2-(14-Methylsulfinyltetradecanoylamino)phenoxy)-butyric acid;

4-(2-(13-n-Propylthiotridecanoylamino)phenoxy)-butyric acid;

4-(2-(12-n-Butylsulfinyldodecanoylamino)phenoxy)-butyric acid;

4-(2-(11-sec-Butylthioundecanoylamino)phenoxy)-butyric acid;

4-(2-(10-phenylthiodecanoylamino)phenoxy)-butyric acid;

4-(2-(10-benzylthiodecanoylamino)phenoxy)-butyric acid;

4-(2-(10-iso-Butylsulfonyldecanoylamino)phenoxy)-butyric acid;

4-(2-(9-t-Butylthiononanoylamino)phenoxy)butyric acid;

4-(2-(8-Ethylsulfonyloctanoamino)phenoxy)butyric acid;

4-(2-(7-Isopropylthioheptanoylamino)phenoxy)butyric acid;

4-(2-(6-Methylthiohexanoylamino)butyric acid;

4-(2-(20-Ethylsulfonyleicosanoylamino)phenylthio)-butyric acid;

4-(2-(19-Isopropylthiononadecanoylamino)phenylthio)-butyric acid;

4-(2-(18-Methylthiooctadecanoylamino)phenylthio)-butyric acid;

4-(2-(17-Ethylthioheptadecanoylamino)phenylthio)-butyric acid;

4-(2-(16-Isopropylhexadecanoylamino)phenylthio)-butyric acid;

4-(2-(15-Methylthiopentadecanoylamino)phenylthio)-butyric acid;

4-(2-(14-Methylsulfinyltetradecanoylamino)phenylthio-butyric acid;

4-(2-(13-Methylsulfonyltridecanoylamino)butyric acid;

4-(2-(12-n-Propylthiododecanoylamino)phenylthio)-butyric acid;

4-(2-(11-n-Butylsulfinylundecanoylamino)phenylthio)-butyric acid;

4-(2-(10-sec-Butylthiodecanoylamino)phenylthio)-butyric acid;

4-(2-(10-phenylthiodecanoylamino)phenylthio)-butyric acid;

4-(2-(10-benzylthiodecanoyiamino)phenylthio)-butyric acid;

4-(2-(9-iso-Butylsulfonylnonanoylamino)phenylthio)-butyric acid;

4-(2-(8-t-Butylthiooctanoylamino)phenylthio)butyric acid;

4-(2-(7-Ethylsulfinylheptanoylamino)phenylthio butyric acid;

4-(2-(6-Isopropylthiohexanoylamino)phenylthio butyric acid;

3-(2-(16-Methylsulfinylhexadecanoylamino)phenoxy)-propionic acid;

4-(2-(15-Methylsulfonylisohexadecanoylamino)phenoxy)-butyric acid;

3-(2-(14-n-Propylthiotetradecanoylamino)phenoxy)-isobutyric acid;

5-(2-(13-n-Butylsulfinyltridecanoylamino)phenoxy)-valeric acid;

5-(2-(12-sec-Butylthiododecanoylamino)phenoxy)-valeric acid;

5-(2-(11-iso-Butylsulfonylisododecanoylamino)-valeric acid;

5-(2-(11-t-Butylthioundecanoylamino)valeric acid;

5-(2-(10-Ethylsulfinyldecanoylamino)valeric acid;

5-(2-(9-Isopropylthiononanoylamino)phenoxy)valeric acid;

6-(2-(9-Methylthiononanoylamino)phenoxy)caproic acid;

6-(2-(8-Ethylthiooctanoylamino)phenoxy)caproic acid;

6-(2-(7-Isopropylthioisooctanoylamino)phenoxy)caproic acid;

7-(2-(7-Methylheptanoylamino)phenoxy)enanthic acid;

7-(2-(6-Methylsulfinylhexanoylamino)phenoxy)enanthic acid;

7-(2-(5-Methylsulfonylisohexanoylamino)phenoxy)-enanthic acid;

2-(2-(12-n-Propylthiododecanoylamino)phenoxy))acetic acid;

2-(2-(11-n-Butylsulfinylundecanoylamino)phenoxy)acetic acid;

2-(2-(10-sec-Butylthiodecanoylamino)phenoxy)acetic acid;

3-(2-(9-iso-Butylsulfonylnonanoylamino)propionic acid;

3-(2-(12-t-Butylthiododecanoylamino)phenylthio)-propionic acid;

3-(2-(11-Ethylsulfinylundecanoylamino)phenylthio)-propionic acid;

4-(2-(11-Isopropylthioundecanoylamino)phenylthio)-butyric acid;

4-(2-(11-Methylthioundecanoylamino)-4-methyl-thiophenoxy)butyric acid;

4-(2-(12-Ethylthiododecanoylamino)phenylthio)-butyric acid;

5-(2-(11-Isopropylthioundecanoylamino)phenylthio)-valeric acid;

5-(2-(10-Methylthiodecanoylamino)phenylthio)valeric acid;

5-(2-(9-Methylsulfinylnonanoylamino)phenylthio)-valeric acid;

5-(2-(12-Methylsulfonyldodecanoylamino)phenylthio)-valeric acid;

5-(2-(11-n-Propylthiodecanoylamino)phenylthio)-valeric acid;

5-(2-(10-n-Butylsulfinyldecanoylamino)phenylthio)-valeric acid;

6-(2-(9-sec-Butylthiononanoylamino)phenoxy)caproic acid;

6-(2-(12-iso-Butylsulfonyldodecanoylamino)phenylthio)caproic acid;

6-(2-(11-t-Butylthioundecanoylamino)phenylthio)-caproic acid;

7-(2-(11-Ethylsulfinylundecanoylamino)-3-methylphenyl-thio)enanthicacid;

7-(2-(11-Isopropylthioundecanoylamino)-4-methylphenyl-thio)enanthicacid;

7-(2-(12-Methylthiododecanoylamino)phenoxy)enanthic acid;

4-(2-(11-Phenylthioundecanoylamino)4-methyl-phenoxy)-butyric acid;

4-(2-(10-Benzylthiodecanoylamino)3-methylphenoxy)-butyric acid;

4-(2-(9-Methylthiononanoylamino)5-methylphenoxy)-butyric acid;

4-(2-(12-Methylsulfinyldodecanoylamino)6-methyl-phenoxy)butyric acid;

4-(2-(11-Methylsulfonyldecanoylamino)3-phenylthio)butyric acid;

4-(2-(10-n-Propylthiodecanoylamino)4-methylphenoxy)-butyric acid;

4-(2-(9-n-Butylsulfinylnonanoylamino)5-fluoromethylphenylthio)butyricacid;

4-(2-(12-sec-Butylthiododecanoylamino)6-methylphenoxy)butyric acid;

5-(2-(11-iso-Butylsulfonylundecanoylamino)-3-methylphenylthio)valericacid;

4-(2-(11-t-Butylthioundecanoylamino)-3-methylsulfonylphenoxy)butyricacid;

4-(2-(11-Ethylsulfinylundecanoylamino)-4-methylsulfonylphenylthio)butyricacid;

4-(2-(12-Isopropylthiododecanoylamino)5-ethylphenoxy)butyric acid;

4-(2-(11-Methylthioundecanoylamino)4-phenylphenoxy)-butyric acid;

4-(2-(10-Ethylthiodecanoylamino)-3,5-dimethylphenoxy)-butyric acid;

4-(2-(9-Isopropylthiononanoylamino)-4-fluoro-phenoxy)-butyric acid;

4-(2-(12-Methylthiododecanoylamino)-5-trifluoromethylphenoxy)butyricacid;

4-(2-(11-Isopropylthio)undecanoylamino)phenoxy)butyric acid,

4-(2-(11-Ethylthio)undecanoylamino)phenylthio)butyric acid,

4-(2-(9-Isopropylthio)nonanoylamino)phenoxy)butyric acid,

4-(2-(10-Isopropylthio)decanoylamino)phenoxy)butyric acid,

4-(2-(12-Isopropylthio)dodecanoylamino)phenoxy)butyric acid,

4-(2-(13-Butylthio)tridecanoylamino)phenoxy)butyric acid,

4-(2-(15-t-Butylthio)pentadecanoylamino)phenoxy)butyric acid,

5-(2-(11-Isopropylthio)undecanoylamino)phenoxy)valeric acid,

4-(2-(11-Ethylsulfinyl)undecanoylamino)-phenoxy)butyric acid,

4-(2-(11-Isopropylsulfonyl)undecanoylamino)-4-methylphenoxy)butyricacid,

4-(2-(11-Ethylsulfinyl)undecanoylamino)-5-methylphenoxy)butyric acid.

All of the compounds described above in the present invention, preparedin accordance with the methods described above, are, as alreadydescribed, can be used to treat prostatic cancer in combination with anantiandrogen, i.e. flutamide, by oral, parenteral or topicaladministration.

In this invention, the antiandrogen, and the 5α-reductase inhibitor areadministered in combination as separate or one single combinedpharmaceutical composition via parenteral or oral means. Preferably theantiandrogen and the 5α-reductase inhibitor are administered orally asseparate compositions.

The amount of each component administered is determined by the attendingclinicians taking into consideration the etiology and severity of thedisease, the patient's condition and age, the potency of each componentand other factors.

The antiandrogen compositions are generally administered in a dosagerange of about 0.20 to 40 mg/kg (body weight) per day with 250 to 750 mgper day, in equally divided doses, three (3) being preferred.

The 5α-reductase inhibitor compositions are generally administered in adosage range of about 0.01 to 1.0 mglkg (body weight) per day with oneto 70 mg per day in one daily dose being preferred.

In the preferred aspect of this invention, the antiandrogen is4'-nitro-3'-trifluoromethylisobutyranilide, i.e. flutamide, which isadministered orally in a daily dose of about 750 mg/kg; the 5α-reductaseinhibitor is finasteride, which is administered orally in a daily doseof about 10 mg/kg.

The antiandrogen and the 5α-reductase inhibitor may be compounded into asingle dosage form suitable for oral or parenteral administration. Atablet or capsule or caplets are particularly convenient forms for oraladministration. Such compositions useful in the present invention aretypically formulated with conventional pharmaceutical excipients, e.g.,spray dried lactose and magnesium stearate into tablets or capsules fororal administration. One or more of the active substances, with orwithout additional types of active agents, can be worked into tablets ordragee cores by being mixed with solid, pulverulent carrier substances,such as sodium citrate, calcium carbonate or dicalcium phosphate, andbinders such as polyvinyl pyrrolidone, gelatin or cellulose derivatives,possibly by adding also lubricants such a magnesium stearate, sodiumlauryl sulfate, "Carbowax" or polyethylene glycols. Of course, tasteimproving substances can be added in the case of oral administrationforms.

As further forms of administration, one can use plug capsules, e.g. hardgelatin, as well as closed softgelatin capsules comprising a softener orplasticizer, e.g. glycerine. The plug capsules contain the activesubstance preferably in the form of a granulate, e.g., in mixtures withfillers, such as lactose, saccharose, mannitol, starches such as potatostarch or amylopectin, cellulose derivatives or highly-dispersed silicicacids. In softgelatin capsules, the active substance is preferablydissolved or suspended in suitable liquids, such as vegetable oils orliquid polyethylene glycols.

The active ingredient components used in accordance with the presentinvention may also be formulated into once-a-day or even longersustained release composition by conventional techniques well known inthe art.

In place of oral administration, the active compounds may beadministered parenterally. In such case, one can use a solution of theactive substance, e.g., in sesame oil or olive oil.

The compositions when administered separately can be contained in asuitable "kit" housing both pharmaceutical compositions inclearly-marked sections and indicating dosage regimens. The kit can bemade of conventional materials.

Following the above treatment using the described regimen, prostatecancer can be significantly inhibited, and in some cases reversed intoremission, when treating such androgen-dependent diseases in accordancewith this invention.

To assist in determining the effect of the prostatic cancer treatment,blood plasma concentrations of testosterone (T), dihydrotestosterone(DHT), and prostate acid phosphatase (PAP) as well as prostate volumeare measured. Lowered concentrations of DHT and prostatic PAP, andreduction in prostate volume, are indicative of successful treatment.The concentrations of the above-listed components in plasma can bemeasured by standard methods well known to those skilled in the art.(See, for example, R. Neri and M. Monahan, Invest. Urology (1972), 10,123-130 for prostatic AP staining and E. Nieschlay and D. L. Loriaux, Z.Klin Chem. Klin Biochem (1972), 4, 164 for radioimmunoassaydeterminations of T.

The prostate volume is measured by rectal examination and/or bytransrectal ultrasonography. Objective assessment of the effect oftreatment is also measured by physical methods well known to theseskilled in the art of nuclear magnetic resonance imaging, as well as byphysical examination.

Further, and more desirably the effect of the combination therapy can bequantified and evaluated by measuring the changes in serumconcentrations of prostate specific antigen (PSA). This is a 35K daltonglycoprotein antigen, associated only with prostatic tissue, discoveredby Wang in 1979. (See Invest Urol, Vol. 17, p. 159 (1979.) Since thatdiscovery, described in Supplement to Biology, Vol. 37, No. 5, pp. 11-16(May 1989) the clinical importance of this new tumor marker has beenrecognized and is now widely accepted as representing a significantlymore effective and reliable tumor marker than prostatic acid phosphatase(PAP).

Protocols for the clinical use of PSA marker in screening tests forprostate cancer to determine staging and to monitor response to therapyare published in the art. (See Journal of Urology, Vol. 142, pp.1011-1017 (October 1989) by M. A. Hudson, et al.)

Using a protocol similar to that described in the above Hudson paper, inwhich PSA was monitored, clinical trials on the effect of finasteridewere conducted. This study is the first clinical trial to evaluate itsefficacy in prostate cancer. Twenty-eight hormone-naive patients withstage D prostate cancer were randomized in a double-blinded fashion toreceive MK-906 (10 mg/day) or placebo. Patients were evaluated at 3 weekintervals by rectal examination and serum PSA, and at 6 week intervalsby bone scan and transrectal ultrasound. Patients were discontinued atthe investigators discretion when PSA levels increased from baseline.After 12 weeks patient on placebo were switched to finasteride.

Thirteen patients received MK-906 and 15 patients received placebo. Astatistically significant decrease in the median percentage change frombaseline in PSA at weeks 3 and 6 occurred in the MK-906 group comparedto the placebo group (-22.9% vs. -2.9%, and -15.1% vs. +9.9%,respectively). Patients who remained on continuous therapy for 24 weekshad 35-40% suppression in PSA. Serum testosterone was not affected whiledihydrosterosterone was markedly lowered by MK-906 to castrate levels.Three patients in each treatment group progressed on bone scan whilenone demonstrated regression.

In summary, a decrease in serum PSA in the MK-906 treatment groupsuggests that MK-906 exerts a tumor suppressive effect on prostatecancer cells. While the magnitude of this effect does not appear similarto medical or surgical castration, it has an excellent safety profileand potential for preservation of sexual potency.

The combination a 5α-reductase inhibitor and antiandrogen, i.e. offinasteride and flutamide, will exhibit an even greater effect onsuppression of prostate cancer cells/tumors in patients with stages (Ato D) of prostatic adenocarcinoma, in which the tumors are stillandrogen-dependent.

The method of preparing the compounds of the present invention, alreadydescribed above in general terms, may be further illustrated by thefollowing examples which should not be construed as being limitations onthe scope or spirit of the instant invention.

CHAPTER 1 Example 1

Methyl 3-oxo-4-aza-5α-androst-1-ene-17β-carboxylate

A suspension of 83.7 g of methyl3-oxo-4-aza-5α-androstane-17-carboxylate* and 126.5 g ofbenzeneseleninic anhydride in 2.09 l of chlorobenzene was heated atreflux for 2 hours. The reflux condenser was switched to a distillationhead and the mixture was distilled slowly to remove water that hadformed in the reaction (2 hours). The solution was evaporated to leave198 g of wet residue. The residue as a solution in dichloromethane waswashed with saturated aqueous NaHCO₃ solution and saturated NaClsolution, then dried and evaporated to leave 172.4 g. This material waschromatographed on 2.56 kg of silica gel eluting first withdichloromethane (5 l) and then with 4:1 dichloromethane acetone. Thedesired product eluted after 8 l and amounted to 53.4 g. It was rinsedwith diethyl ether and dried to leave 49.5 g, of the title compound m.p.278-280° C. In a similar fashion the following compounds were convertedto their corresponding 1,2-unsaturated derivatives: ##STR63##

Example 2

Methyl 4-methyl-3-oxo-4-aza-5α-androst-1-ene-17-carboxylate

A suspension of 25 g of the product of Example 1 and 2.25 g of sodiumhydride in 500 ml of dry dimethylformamide was stirred under nitrogenfor 15 minutes. Methyl iodide (15 ml) was added dropwise and the mixturewas stirred for 30 minutes at room temperature. Additional (5 ml) methyliodide was added and the mixture was heated at 50° C. for 2 hours. Aftercooling the mixture was diluted with water to a volume of 2 liters. Thesolid was separated after cooling and amounted to 25.4 g, m.p. 159-161°C.

In a similar fashion the following compounds were converted to theircorresponding 4-methyl derivatives: ##STR64##

Example 3

S-(2-Pyridyl) 4-methyl-3-oxo-4-aza-5α-androst-1-ene-17β-thiocarboxylate

A suspension of 25 g of the product of Example 2 in 125 ml of methanolwas treated with a solution of KOH (*12.5 g) in 12.5 ml of water. Afterrefluxing for 4 hours, the solution was acidified with 6 NHCl and thenwas diluted with water. The crude acid (23.32 g) was separated, driedand had m.p. 300° C.

The crude, dry acid (23 g), triphenylphosphine (36.45 g) and2,2'-dipyridyldisulfide (30.4 g) were suspended in 138 ml of toluenewith stirring for 3 hours at room temperature. The reaction mixture wasdirectly chromatographed on a column of 4.5 kg of silica gel elutingwith 9:1 ethyl acetate-acetone to give 20.4 g of the desired product,m.p. 218-220° C.

Continued elution with acetone gave 5.2 g of the methanol additionproduct, S-(2-pyridyl)1α-methoxy-4-methyl-3-oxo-4-aza-5α-androstane-17β-thiocarboxylate, m.p.221-223° C. as a by-product.

3A. In a similar fashion the product of Example 1 was converted intoS-(2-pyridyl) 3-oxo-4-aza-5α-androst-1-ene-17β-thiocarboxylate, m.p.230-232° C.

3B. In a similar manner methyl 3-oxo-4-aza-5α-androstane 17β-carboxylatewas converted into S-(2-pyridyl)3-oxo-4-aza-5α-androstane-17β-thiocarboxylate, m.p. 232-234° C.

Example 4

N-t-butyl 4-methyl-3-oxo-4-aza-5α-androst-1-ene-17β-carboxamide

Anhydrous t-butylamine was added to a suspension of 2.5 g of thepyridylthioester of Example 3 in 70 ml of tetrahydrofuran. After 60minutes exposure, the resulting solution was evaporated and the residuewas chromatographed on 125 g of silica gel. Elution with 20:1 ethylacetate dichloromethane afforded 1.5 g of the product, m.p. 152-154° C.

When the example is repeated using an appropriate amine and anappropriate pyridylthioester, the following products were obtained:

4b: N-t-butyl 3-oxo-4-aza-5α-androstane-17β-carboxamide, m.p. 275-276°C.

4c: N-(2,4,4-trimethyl-2-pentyl)4-methyl-3-oxo-4-aza-5α-androst-1-ene-17β-carboxamide, m.p. 168-170° C.

Example 5

5-Oxo-3,5-secoetian-3,20-dioic acid

To a solution of 200 g of 3-oxo-4-etien-17β-oic acid in 3.5 l oft-butanol at 80° was added a solution of 198.4 g of sodium carbonate in474 ml of water. A warm (65° C.) solution of 948.5 g of sodiummetaperiodate and 6.95 g of permanganate in 3.5 l of water was added atsuch a rate that the reaction mixture was maintained at 80° C. Afteraddition the mixture was heated at reflux for one hour. The mixturestood at room temperature overnight. The inorganic salts were removed byfiltration and the cake was washed with 225 ml of water. A solution of5% aqueous sodium bisulfite was added to reduce the iodine that waspresent. The t-butanol was removed under reduced pressure and theaqueous residue was acidified with conc. hydrochloric acid. Theseparated gum was extracted into dichloromethane and was washed with 5%aqueous sodium bisulfite, saturated sodium chloride solution, then driedand concentrated to an off-white residue (214 g). Crystalline materialwas obtained by suspending the residue in ether and diluting with hexaneto give 152 g, m.p. 189-192° C.

Example 5B

3-Oxo-4-aza-5-etien-20-oic acid

A suspension of 64.7 g of the dioic acid of Step 5 in 350 ml of ethyleneglycol was treated with 80 ml of liquid ammonia. The resulting solutionwas heated at a rate of 3°/min. up to 180° C. and was held at thattemperature for 15 minutes. After cooling, 1 liter of water was addedand the mixture was acidified with 10% hydrochloric acid to a pH of 1.5.The product was removed and washed with water, then air dried to leave57.5 g of the product, m.p. 310° C.

Example 5C

3-Oxo-4-aza-5α-etian-20-oic acid

A solution of 136 g of the 5-acid of Example 5B in 16.32 ml of aceticacid was hydrogenated at 60° C. in the presence of platinum catalyst(from 16.32 g of PtO₂) at 40 psig for 3 hours. The catalyst was removedand the solution concentrated to give 128.2 g of crude product. Thematerial was washed well with 3 l of water then filtered an air dried toleave 125 g of the white solid, m.p. 310°.

This material is also obtained by saponification of methyl3-oxo-4-aza-5α-androstane-17β-carboxylate (methyl3-oxo-4-aza-5α-etien-17β-oate) in 7% methanolic potassium hydroxidefollowed by an acidic work-up.

Example 5D

N-(2,4,4-trimethyl-2-pentyl)3-oxo-4-aza-5α-androstane-17β-carboxamide

A solution of 5.0 g of the product of Example 5C, 3.35 g ofdicyclohexylcarbodiimide and 3.18 g of 1-hydroxybenztriazole in 500 mlof dichloromethane was stirred at room temperature overnight. The solidwas separated by filtration and the filtrate was treated with2,4,4-trimethyl-2-pentylamine (t-octylamine). This solution stood atroom temperature for 64 hours. A small amount of solid was removed andthe solution was washed successively with 10% aqueous sodium hydroxide,water, 10% hydrochloric acid and saturated aqueous sodium chloride.After drying and concentration the crude product was eluted through 240g of silica gel with 3:7 acetone-dichloromethane to give 5.5 g of theproduct, m.p. 250-251° C.

Example 5E

Example 5D is repeated using t-butylamine in place of2,2,4-trimethyl-2-pentylamine to obtain N-t-butyl3-oxo-4-aza-5α-androstane-17β-carboxamide, m.p. 274-276° C.

Example 6

Synthesis of 17β(N-1-adamantyl-carbamoyl)-4-aza-5α-androst-1-en-3-one

100 mg of the 17-methyl ester (0.305 mmoles) from Example 1 wassuspended in 3.0 ml of THF (dried over molecular sieves 3A), and thenwas added 183.0 mg of 1-adamantanamine (1.2 mmoles). The suspension wascooled to 5-10° C. and then 590 μl of 2.0 M solution, of EtMgBr in THFwas added. The resulting mixture was allowed to stir for 10 minutes, andthen refluxed for 1-2 hours under N₂. The mixture was cooled to 0° C.and then quenched with saturated solution of NH₄ Cl (about 10 ml.). Theorganic layer was separated and the aqueous layer extracted with threevolumes CH₂ Cl₂.

The organic layers were combined, washed 2 times with H₂ O, twice withsaturated sodium chloride, and dried over MgSO₄, filtered and evaporatedto dryness in vacuum. Crystallization from EtOAc afforded 75.0 mg ofproduct. Recrystallization from MeOH and drying at 110° C. for 2hours/0.1 mm gave product, mpt. 305-306° C. Molecular weight (by FAB)showed M⁺ =451: Calculated=451.

Anal. Calcd. for C₂₉ H₄₂ N₂ O₂ : C,77.28; H,9.40; N,6.21. Found:C,76.84; H,9.73; N,5.93.

Example 7

Synthesis of 17β(N-2-adamantyl-carbamoyl)-4-aza-5α-androst-1-en-3-one

Following the above-described general procedure of Example 6 bututilizing 2-adamantamine (prepared by aqueous neutralization of thehydrochloride and EtOAc extraction and isolation) in place of1-adamantamine, and carrying out the reflux for 7 hours rather than 1-2hours, the title compound is prepared, mpt. 284-285° C.

Example 8

Synthesis of 17β(N-1-adamantylcarbamoyl)-4-aza-5α-androstane-3-one

100.0 mg of the adamantyl derivative produced in Example 6 was dissolvedin 5.0 ml of dry THF. 300 mg of 5% Pd/C was added and the mixture washydrogenated for 6.0 hrs. at R.T. at 40 psi. The mixture was filteredthrough celite, the cake washed with THF (3 times) and solventevaporated under vacuum to yield 97.0 mg. of crude above-titled product.NMR showed absence of olefins. The crude material was placed on 15.0 gsilica gel column, and eluated with 1:1(CH₂ Cl₂ : acetone).

Collected fractions afforded a single spot material by TLC weighing77.98 mg. NMR was in excellent agreement with the proposed structure.Recrystallized from EtOAc to yield 65.59 mg of the above-titled product,mp. 323-324° C.

Anal. Calcd. for C₂₉ H₄₄ O₂ N₂ 1/4 H₂ O: C,76.18; H,9.81; N,6.13. Found:C,75.91; H,9.97; N,6.06.

Example 9

Synthesis of17β(N-1-adamantylcarbamoyl)-4-methyl-4-aza-5α-androst-1-en-3-one

120 mg of the thiopyridyl ester of Example 3 was suspended in 20 ml ofdry THF, to the suspension was added 175.0 mg of 1-adamantanamine underN₂. The reaction was carried out at R.T. for 16 hours under N₂. Thereaction was monitored by silica gel TLC, using 1:1 acetone: hexane. Theproduct was separated on TLC 20 cm×20 cm, 1000 μm silica gel plate,eluted with 1:1 (acetone/hexane). The product was crystallized fromethyl acetate, to give 50.0 mg of pure material m. pt. 202-205° C.Molecular Weight (FAB) showed 465; Calc: 465. Recrystallization afforded19.14 mg of the above-titled product, m.pt. 202-202.5° C.

Anal. Calcd for C₃₀ H₄₄ N₂ O₂.H₂ O: C,74.64; H,9.60; N,5.80. Found:C,74.32; H,9.47; N,5.89

Example 10

Hydrolysis of Methyl-3-oxo-4-aza-5α-androstane-17β-carboxylate

The 17β-androstane carboxylate starting material of Example 1 washydrolyzed with 7% KOH in isopropanol or aqueous methanol, followed byan acidic work-up to give the corresponding 17β carboxylic acid whichwas utilized in Example 11.

Example 11

N-(1-adamantyl)-3-oxo-4-aza-5α-androstane-17β-carboxamide

A solution of 5.0 g of the product of Example 10, 3.35 g ofdicyclohexylcarbodiimide and 3.18 g of 1-hydroxybenztriazole in 500 mlof dichloromethane was stirred at room temperature overnight. The solidwas separated by filtration and the filtrate was treated with1-adamantamine. This solution stood at room temperature for 64 hours,then filtered, and the solution was washed successively with 10%hydrochloric acid and saturated aqueous sodium chloride. After dryingwith MgSO₄, it was filtered and concentrated. The crude product waseluted through 240 g of silica gel with 3:7 (acetone-dichloromethane) togive 5.5 g of the above-titled product, m.p. 323-324° C.

Example 12

Synthesis ofBenztriazol-1-yl-3-oxo-4-methyl-4-aza-5α-androstan-17β-carboxylate

A suspension of 83.7 g ofmethyl-3-oxo-4-methyl-4-aza-5α-androstane-17β-carboxylate. (SeeRasmusson, et al. J. Med. Chem 29, 2298-2315, 1986) was hydrolyzed with7% KOH in aqueous methanol, followed by an acidic work up to give thecorresponding 17β-carboxylic acid.

The acid was readily converted into benzotriazyl-1-yl-3-oxo-4methyl-4-aza-5α-androstane 17β carboxylate as described in Example 13.The activated ester (the benzotriazoyl derivative) was purified on TLC(4 plates, 20 cm×20 cm×20 cm×1000 μm silica gel) eluted with 4:96(MeOR-CHCl₃). The isolated product was washed with ether to give theactive ester m.pt. 198-200° C. with decomposition.

Example 13

Synthesis of 17β(N-1-adamantylcarbamoyl)-4-methyl-4-aza-5α-androstan-3-one

100.0 mg of the 4-methyl-4-aza-benzotriazole derivative prepared asdescribed in Example 12, was dissolved in 20.0 ml CH₂ Cl₂. To the clearsolution was added 127 mg of 1-adamantamine. The reaction mixture wasstirred overnight at R.T./N₂.

Crystallization from EtOAc after filtering the solution through TeflonAcrodisc CR afforded 26.32 mg, m.pt. 210-217° C. The product was furtherpurified on 1.0 g silica gel column (EM silica gel) with 1:1(acetone-hexane) as eluant to give after recrystallization (ethylacetate) 21.75 mg of white needles of the above-titled product, m.pt.203-205° C.

Anal. Calcd. for C₃₀ H₄₆ N₂ O₂.1.5 H₂ O: C,73.58; H,9.68; N,5.62; Found:C,73.15; H,9.30; N,5.67.

Example 14

Diastereomeric Synthesis of17β(N-exo-2-norbornanylcarbamoyl)-4-aza-5α-androst-1-en-3-one)

100.0 mg of the corresponding 4-H thiopyridyl ester of Example 3,prepared by the procedure of Example 3, but utilizing the 4-H methylester product of Example 1, (See Rasmusson et al. J. Med. Chem. Vol. 29,pp. 2298-2315 (1986), was dissolved in 3.0 ml of dry THF under N₂. Tothe clear solution was added 477 μl of (±) racemicexo-2-aminonorbornane. Allowed the reaction to proceed for 16 hours atR.T./N₂. The reaction mixture was evaporated to dryness in vacuum. Theresidue was dissolved in chloroform. The organic layer was washed with2.5 N HCl acid (3 times); 3 times with water; 3 times with saturatedNaCl solution, dried over MgSO₄, filtered and evaporated to dryness invacuum to afford 56.3 mg of a racemic diastereomeric mixture.

The crude product was chromatographed on TLC (2 plates, 20 cm×20 cm×500μm silica gel) eluted with 70:30 (CHCl₃ :acetone) to yield 43.4 mg ofthe above-titled product. Recrystallization from EtOAc yielded 30 mgproduct, m.pt 245-245.9° C.

NMR (CDCl₃) confirmed the above structure. FAB mass spectrum calcd. forC₂₆ H₃₈ O₂ N₂ : m/e 411; Found: 411. Anal. Calcd. for C₂₆ H₃₈ O₂ N₂.H₂O: C,72.82; H,9.40; N,6.58. Found: C,73.21; H,9.20; N,6.25.

Example 15

Synthesis of17β(N-1-adamantylmethylcarbamoyl)-4-aza-5α-androst-1-en-3-one

200.0 mg of the 4-H thiopyridyl aza steroid, used in Example 14, wassuspended in 2.0 ml of dry THF.

To the suspension was added 400 μl of 1-aminomethylene adamantane viasyringe at R.T./N₂. After several minutes, a yellow clear solutionresulted and after 1/2 hr., precipitation occurred. The reaction wasallowed to proceed overnight/N₂. Diluted with CH₂ Cl₂, washed with 10%NaOH, two times, then with H₂ O two times, followed by 10% HCl (twotimes), H₂ O (two times), and finally two times with satd. NaClsolution.

The organic layer was dried over MgSO₄, filtered, concentrated in vacuoto obtain the product, as shown by NMR, recrystallized from EtOAc, toyield 149.0 mg product, m.pt 255-257° C. with decomposition.

FAB Mass Spectrum, Calcd: m/e 464+1=465: Found 465.

Example 16

Synthesis of 17β(N-2-adamantylcarbamoyl)-4-aza-5α-androstan-3-one

A mixture of 1.09 grams17β-(N-2-adamantylcarbamoyl)-4-aza-5α-androst-1-en-3-one (See Example 10for preparation), 150 ml of ethanol, and 1.0 g. of 30% Pd/C washydrogenated overnight with shaking under 45 psig. hydrogen pressure.The suspension was filtered to remove catalyst, and evaporated todryness to yield a grey residue. This was chromatographed by elution ona 200 ml silica gel column with 40:60 acetone/methylene chloride eluantto yield 1.0 g of solid, mp. 294-296° C.

Anal. Calcd. for C₂₉ H₄₄ N₂ O₂.0.2H₂ O; Calcd. C, 76.33; H, 9.80; N,6.14; Found C, 76.23; H, 9.86; N, 5.92; Mass Spec. Analysis by electronimpact showed MW of 452.

Example 17

Synthesis of17β-(N-2-adamantylcarbamoyl)-4-aza-4-methyl-5α-androst-1-en-3-one

A suspension of 500 mg of17β-(N-2-adamantylcarbamoyl)-4-aza-5α-androst-1-en-3-one, as prepared inExample 16, 10 ml sieve-dried DMF, 140 mg NaH, were heated and stirredat 70° C. under a nitrogen atmosphere for 18 hours. Cooled to roomtemperature and then added 0.4 ml methyl iodide dropwise with stirringwhich was continued at 50° C. for 3 hours. The reaction mixture was thentreated by cooling to room temperature, followed by the addition of 15ml water. The mixture was extracted with 3×20 ml of CH₂ Cl₂. The organiclayers were combined, washed with brine, dried and evaporated to yield awhite crystalline residue. Recrystallization from ethyl acetate/CH₂ Cl₂yielded a pure white solid, mp 246-248° C.

Analysis calculated for C₃₀ H₄₄ N₂ O₂.0.3H₂ O; Calcd. C, 76.65; H, 9.56;N, 5.95; Found C, 76.50; H, 9.75; N. 5.84 ; Mass spectroscopy showed amolecular weight of 464.

Example 18

Synthesis of17β-(N-2-adamantylcarbamoyl)-3-oxo-4-methyl-4-aza-5α-androstane

17β-(N-2-adamantylcarbamoyl)-4-methyl-4-aza-androsten-1-en-3-one, (200mg) as prepared in Example 17, were placed into 25 ml absolute ethanolwith 200 mg 30% Pd/C hydrogenation catalyst. The suspension was rockedovernight under 40 psig hydrogen pressure.

The suspension was filtered, and the filtrate evaporated to dryness. Theresidue was recrystallized from hot ethyl acetate to give a whitecrystalline solid, mp. 113-115° C. Calcd. for C₃₂ H₅ ON₂ O₃.0.5 EtOAc

Calcd: C, 75.25, H, 9.86, N, 5.48; Found C, 75.07; H, 9.52; N, 5.28;Mass spectroscopy depicted a molecular weight of 466 for thenon-solvated molecule.

Example 19

Synthesis of 17β-(N-methyl-N-2-adamantyl)carbamoyl-4-methyl-4-aza-androst-1-en-3-one

17β-(N-2-adamantyl)carbamoyl-4-aza-androst-1-en-3-one (5.0 g) and 1.5 gsodium hydride in 100 ml dry DMF were stirred under dry nitrogen for 3hours at 40° C. The reaction was cooled to room temperature and about 4ml of methyl iodide was added dropwise and allowed to stir at roomtemperature for one hour. The reaction was cooled in an ice bath and alarge excess of about 250 ml, water was added. The aqueous mixture wasextracted with CH₂ Cl₂ (3×100 ml), the organic extracts combined, washedwith H₂ O, brine, and then evaporated to dryness to yield crude product.The crude product was eluted on an HPLC column (Si gel) with 10/1acetone/CH₂ Cl₂ to yield 2 peaks having retention times of 3 CV(B) and3.8 CV(A). Peak (A) was analyzed as per the 4-methylaza titled productof Example 15. The second product (B) was analyzed as the4-methylaza-17β-(N-methyl-N-2-adamantyl/carbamoyl analog, i.e. thetitled compound, mp. 163-165.

Calcd. for C₃₁ H₄₆ N₂ O₂ ; Calcd. C, 77.77; H, 9.68; N, 5.85; Found C,77.29; H, 9.79; N, 5.77; Mass spectrometry showed a molecular weight of478.

Example 20

Synthesis of 17β-(N-methyl-N-2-adamantylcarbamoyl)4-aza-4-methyl-androstan-3-one

The crude reaction mixture from Example 19 (4.6 g) was dissolved in 200ml ethanol and together with 1.0 g 30% Pd/C was hydrogenated under 40-45Psig a hydrogen atmosphere at room temperature overnight. The mixturewas filtered, residue washed with ethanol. The ethanol solution wasevaporated to dryness to yield a crude mixture. Recrystallized from CH₂Cl₂ /diethyl ether/hexane to yield 800 mg of the pure monomethylandrostane compound of Example 16, mp 113-115° C. Second and third cropswere combined with mother liquor and treated by HPLC as in Example 17 toyield the dimethylated title compound, mp 180-182° C.

Anal. Calcd. for C₃₁ H₄₈ N₂ O₂ ; Calcd. C, 77.45; H, 10.06; N, 5.83;Found C, 77.26; H, 9.87; N, 5.82; Mass spectrometry showed a molecularweight of 480.

Example 21

N-t-Butyl Androst-3,5-diene-17β-carboxamide-3-Carboxylic Acid

(a) N-t-butyl androst-3,5-diene-3-bromo-17β-carboxamide

To a solution of oxalic acid (0.0011 mol, 0.1 g) and oxalyl bromide(0.0211 mol, 3 ml) in 15 ml of sieve dried toluene was added over a onehour period 1 g (0.003 mol) of androst-4-ene-3-one 17β-carboxylic acid.The reaction was stirred at room temperature for 2 hours and then it wasconcentrated in vacuo. The excess oxalyl bromide was removed byazetoroping with toluene. The resulting brown oil was redissolved intoluene, cooled to 0° C. and then 10 ml t-butylamine (7.0 g) in 30 ml oftoluene was added dropwise over 15 minutes. Once the addition wascomplete, the reaction was stirred at 0° C. for 15 minutes and then itwas kept at -20° C. for 19 hours. The reacton mixture was allowed towarm to room temperature and then stirred at 25° C. for one hour. Thevolatiles were removed in vacuo. The residue was partitioned betweenchloroform/water, the layers were shaken together and separated and thenthe aqueous phase was back-extracted twice with chloroform. The combinedorganic extracts were washed with water (2×) and then dried withanhydrous magnesium sulfate. The crude product was purified by flashchromatography on silica, eluting with 20% ethyl acetate in hexane, togive 1.06 g of the title compound, a white solid.

(b) N-t-Butyl Androst-3,5-diene-17β-carboxamide-3-carboxylic acid

To a solution of N-t-Butyl Androst-3,5-diene-3-bromo-17β-carboxamide(0.5 g, 0.00115 mol) in 5 ml of tetrahydrofuran, cooled to -78° C. (dryice/acetone bath) under argon, was added dropwise 1.5 ml (0.00375 mol)of a 2.5 M solution of n-butyl lithium in hexane. The reaction mixturewas stirred at this temperature for one hour and then carbon dioxide wasbubbled into the reaction for 45 minutes, via a concentrated sulfuricacid tower. The reaction mixture was allowed to warm to room temperatureand then it was diluted with water, aqueous HCl solution and chloroform.The layers were shaken together and separated, with the aqueous phasebeing back-extracted with chloroform (2×). The combined organic extractswere washed with water (2×), and brine (1×) and then dried withanhydrous magnesium sulfate. The solvents were removed under reducedpressure give 0.6 g of a crude solid. This material was slurried withhexane and a white solid was isolated (0.43 g). The title compound wasrecrystallized from acetonitrile, m.p. 247-250°.

CHAPTER 2 Example 1

Methyl 3-oxo-4-aza-5α-androst-1-ene-17β-carboxylate

A suspension of 83.7 g of methyl3-oxo-aza-5α-androstane-17β-carboxylate* and 126.5 g of benzeneseleninicanhydride in 2.09 l of chlorobenzene was heated at reflux for 2 hours.The reflux condenser was switched to a distillation head and the mixturewas distilled slowly to remove water that had formed in the reaction (2hours). The solution was evaporated to leave 198 g of wet residue. Theresidue as a solution in dichloromethane was washed with saturatedaqueous NaHCO₃ solution and saturated NaCl solution, then dried andevaporated to leave 172.4 g. This material was chromatographed on 2.56kg of silica gel eluting first with dichloromethane (5 liters) and thenwith 4:1 dichloromethane-acetone. The desired product was eluted with 8liters of the above-mixed solvent and evaporated to dryness in vacuo toyield 53.4 g solid. It was washed with diethyl ether and dried to leave49.5 g of the above-titled product, m.p. 278-280° C.

Example 2

S-(2-Pyridyl)-3-oxo-4-aza-5α-androst-1-ene-17β-thiocarboxylate

A suspension of 25.0 g of the above product from Example 1 wassaponified with 12.5 g of KOH in 150.0 ml of 5:1 CH₃ OH--H₂ O underreflux conditions for 4 hours/N₂. The mixture was cooled to 25° C. andacidified to pH<2. Water (175 ml) was added gradually with stirring toleave a crystalline precipitate which was collected and washed withwater.

After drying, the product amounted to 25 g., m.pt 313-315° C. withdecomposition.

The crude dry acid (23.0 g) was suspended in 210 ml of toluene, and tothe suspension was added triphenylphosphine (56.0 g) and 2,2'-dipyridyldisulfide (48.3 g), and the mixture was stirred at 24° C. overnight/N₂.The reaction mixture was placed on a column of silica gel (1.3 kg) andwas eluted with 1:1 (acetone/CH₂ Cl₂). The desired thioester elutedslowly, and after rinsing with ether, yielded 36.8 g of the above-titledproduct, m.p. 232-235° C.

Example 3

22-Methyl-4-aza-21-nor-5α-chol-1-ene-3,20-dione ##STR65##

To a solution of 7.2 g ofS-(2-pyridyl)-3-oxo-4-aza-5α-androst-1-ene-17α-thiocarboxylate in 288 mlof tetrahydrofuran was-added at -78° C. 33.6 ml of 1.3M S-butylmagnesiumchloride. After 30 minutes at -78° C. the solution came to roomtemperature and was treated with saturated aqueous NaCl solution. Theproduct was extracted into dichloromethane and was washed with saturatedaqueous NaCl solution and 10% aqueous NaOH solution, then dried andconcentrated. The residue was eluted through 430 g of silica gel with9:1 dichloromethane-acetone to give 4.5 g of the product, m.p. 246-249°C.

When the procedure is repeated using the following reagents, theindicated product is obtained.

    ______________________________________                                        Starting                                                                        Material Reagent Product                                                    ______________________________________                                        S-(2-pyridyl)3-                                                                           2-pyrrolyl mag-                                                                             17β-(2-pyrrolyl-                                 oxo-4-aza-5α- nesium chloride carbonyl)-4-aza-                          androst-l-ene-  5α,-androst-1-ene-                                      17β-thiocarboxylate  3-one                                                 m.p. 294-296° C.                                                     S-(2-pyridyl)3- sec-butyl mag- 4,22-dimethyl-4-                               oxo-4-methyl-5α- nesium chloride aza-21-nor-5α-                   androst-1-ene-17β-  chol-1-ene-3,20-dione                                thiocarboxylate  m.p. 134-136° C.                                      S-(2-pyridyl)3- 2-pyrrolyl mag- 4-methyl-17β-(2-                         oxo-4-methyl-4- nesium chloride pyrrolylcarbonyl)-                            aza-5α-androst-  4-aza-5α-androst-                                1-ene-17β-thio-  1-ene-3-one                                             carboxylate  m.p. 234-238° C.                                          S-(2-pyridyl)3- isobutyl mag- 23-methyl-4-aza-                                oxo-4-aza-5α- nesium chloride 21-nor-5α-                          androst-ene-17β-  cholane-3,20-                                          thiocarboxylate  dione                                                          m.p. 220-222° C.                                                   ______________________________________                                    

Example 4

22-Methyl-4-aza-21-nor-5α-chol-1-ene-3,20-dione ##STR66##

A solution of 21 g of 22-methyl-4-aza-21-nor-5α-cholane-3,20-dione and29.49 g of benzeneseleninic anhydride in 552 ml of chlorobenzene wasrefluxed with water separation for 4 hours. The mixture was concentratedand the residue was redissolved in dichloromethane. After washing with10% aqueous sodium hydroxide, then 10% hydrochloric acid and saturatedaqueous sodium chloride the solution was dried and concentrated to 45 gof yellow residue. This was chromatographed on 1.5 kg of silica gelpacked in dichloromethane and eluted with ethyl acetate to give 10.6 gof the product, m.p. 248-251° C.

When the procedure is repeated using23-methyl-4-aza-21-nor-5α-cholane-3,20-dione as starting material theproduct obtained is 23-methyl-4-aza-21-nor-5α-chol-1-ene-3,20-dione,m.p. 283-286° C.

Example 5

17β-(phenylcarbonyl)-4-aza-5α-androst-1-ene-3-one

To a stirred suspension of 43 g ofS-(2-pyridyl)-3-oxo-4-aza-5-alpha-androst-1-ene-17-beta-thiocarboxylatein 500 ml of anhydrous tetrahydrofuran (THF) was added at -78° C. a THFsolution of 157 ml of 2N phenylmagnesium chloride over 60 minutes. Afterstirring at -78° C. for 60 minutes, the mixture was brought to -30° C.and was quenched by addition of 10% HCl while maintaining thetemperature below -20° C. After warming to 0° C., the mixture wasdiluted with 2000 ml of water and extracted with 4000 ml ofdichloromethane in portions. The organic layer was washed sequentiallywith water, 1N sodium hydroxide, water and saturated sodium chloridesolution. Drying with MgSO4 and concentration afforded 37.5 g of crudeproduct. Recrystallization from dichloromethane/ethyl acetate gave thetitle phenyl ketone (30.4 g, 77% yield). m.p. 290-291° C.

    ______________________________________                                                     Calc Found                                                       ______________________________________                                        N              3.61   3.56                                                      C 77.48 77.16                                                                 H 8.26 8.19                                                                 ______________________________________                                    

Example 6

17-beta-4-fluorophenycarbonyl-4-aza-5-alpha-androst-1-ene-3-one

The procedure of Example 5 was repeated except usingp-fluorophenylmagnesium bromide as the Grignard reagent and the titlecompound was obtained. m.p. 315-315.5° C.

Example 7

17β-(cyclohexylcarbonyl)-4-aza-5α-androst-1-ene-3-one

To a suspension of 34.8 g of the thiopyridyl ester of Example 2 in 700ml of anhydrous THF was added at -65 degrees C. 130 ml of a 2 M ethersolution of cyclohexyl magnesium chloride over a period of 20 minutes.After stirring at -70 degrees C. for 60 minutes the solution was warmedand stirred at -10 degrees C. for 60 minutes. The mixture was dilutedwith 500 ml of dichloromethane and then dropwise with dichloromethane,the phases were separated and the organic layer was treated sequentiallywith water, 1 N sodium hydroxide, water and saturated sodium chloridesolution. The organic solution was decolorized with charcoal, filteredand concentrated to a residue which was crystallized from ethyl acetateto give 28.2 of the title compound, m.p. 271.5-277 degrees C.

Example 8

The title compound of Example 7 was also prepared by the followingprocedure.

To a mixture of 150 g of methyl3-oxo-4-aza-5-alpha-androst-1-ene-17-beta-carboxylate in 2800 ml ofanhydrous THF was added with stirring at less than 0 degrees C. internaltemperature 678 ml of a 2 N ether solution of cyclohexyl magnesiumchloride. The solution was then refluxed for 6 hours. The cooled (lessthan 10 degrees C.) reaction mixture was acidified with 10% HCl solutionand was extracted with dichloromethane. The organic layer was washedsequentially with water, saturated NaHCO3 solution and saturated NaClsolution. Drying (MgSO4) and evaporation left 163 g of crude cyclohexylketone. Recrystallization from dichloromethane/ethylacetate gave 131 gof the pure material.

m.p. 269-270 degrees C.

    ______________________________________                                                     % Calc.                                                                             Found                                                      ______________________________________                                        N              3.61    3.61                                                     C 77.37 77.37                                                                 H 9.74 10.13                                                                ______________________________________                                    

Example 9

17-beta-(cyclopentylcarbonyl)-4-aza-5-alpha-androst-1-ene-3-one

When the procedure of Example 7 or 8 was repeated usingcyclopentylmagnesium chloride, the title compound was obtained:

m.p. 272-273 degrees C.

    ______________________________________                                                     Calc.                                                                              Found                                                       ______________________________________                                        N              3.66   3.78                                                      C 75.25 74.89                                                                 H 9.60 9.54                                                                 ______________________________________                                    

Example 10

17-beta-(cyclobutylcarbonyl)-4-aza-5-alpha-androst-1-ene-3-one

When the procedure of Example 7 or 8 was repeated usingcyclobutylmagnesium chloride, the title compound was obtained:

m.p. 288-289 degrees C.

    ______________________________________                                                     % Calc                                                                              Found                                                      ______________________________________                                        N              3.94    3.87                                                     C 77.71 78.06                                                                 H 9.36 9.61                                                                 ______________________________________                                    

Example 11

Synthesis of 17-β-(4-Phenylbenzoyl)-4-aza-5α-androst-1-en-3-one

To a suspension of 258.0 mg of dry activated magnesium chips in 5.0 mlof dry THF was added 932.0 mg of 4-bromobiphenyl in 5.0 ml of dry THFunder N₂. The reaction was run in an ultrasonic bath at a temperaturerange of 24-30° C. To the well-agitated mixture was added dropwise 30 μlof 1,2-dibromoethane/N₂. The reaction was allowed to proceed for 1-11/2hours at 28° C./N₂. The concentration of the Grignard reagent was 4.0mmoles in 10.0 ml of dry THF.

The steroid from Example 2 (205.0 mg, 0.5 mmol of thiopyridyl ester) wassuspended in 2.0 ml of dry THF, cooled to -80° C. and the above Grignard3.80 ml was added via syringe to the steroidal suspension over 5-10minutes/N₂. The reaction was allowed to proceed for 1 hour at -80° C./N₂and then at -10° C. for an additional hour/N₂. The solution was dilutedwith 10.0 ml of methylene chloride and quenched with saturated aqueoussolution of NH₄ Cl to pH=4. The organic layers were separated, washed 3times with water, 3 times with saturated sodium chloride, dried overMgSO₄, filtered, and evaporated under vacuum to afford 156.2 mg of crudeproduct. Crystallization from EtOAc gave the above-titled product in98.58 mg, m.pt. 290° C.-290.5° C.

Anald. Calcd. for C₃₁ H₃₅ NO₂ : C,82.08; H,7.78; N,3.09; Found: C,81.84;H,8.01; N,3.06. FAB: Calc. for C₃₁ H₃₅ NO₂ : 453; Found: 453.

Example 12

17-β-(3-Phenylbenzoyl)-4-aza-5α-androst-1-en-3-one

To a suspension of 258.0 mg of dry activated magnesium chips in 8.0 mlof dry THF was added 932.0 mg of 3-bromobiphenyl in 2.0 ml of dry THFunder N₂. The reaction was run in an ultrasonic bath at a temperaturerange of 24-30° C. To the well-agitated mixture was added dropwise 30microliters of 1,2-dibromoethane/N₂. The concentration of the Grignardreagent was 4 mmoles in 10.0 ml of dry THF.

The steroid from Example 2, 205.0 mg (0.5 mmoles) was suspended in 2.0ml of dry THF, cooled to -80° C. and the above prepared Grignard, 3.80ml, was added via syringe to the steroidal suspension over 5-10minutes/N₂. The reaction was allowed to proceed for 1 hour at -80° C./N₂and then at -10° C. for an additional hour/N₂. The solution was dilutedwith 10.0 ml of methylene chloride and quenched with a saturated aqueoussolution of NH₄ Cl to pH=4. The organic layers were separated, washed 3times with water, 3 times with saturated sodium chloride, dried overMgSO₄, filtered, and evaporated under vacuum. Crystallization from ethylacetate afforded 122.84 mg of product. The material was purified on 20.0g of silica gel column using 70:30 (CHCl₃ -acetone) as eluant, to give asingle spot material 117.0 mg of the above-titled compound, m.pt.184-185° C.

Anald. Calcd. for C₃₁ H₃₅ NO₂ : C,82,08; H,7.78; N,3.09; Found: C,82.28;H,8.04; N,2.98. FAB: Calcd. for C₃₁ H₃₅ NO₂ : 453; Found: 453.

Example 13

Synthesis of 17-β-(4-Methylthiobenzoyl)-4-aza-5-α-androst-1-en-3-one

To a suspension of 250.0 mg of dry activated magnesium chips in 8.0 mlof dry THF was added 812.0 mg of p-bromophenyl methyl sulfide in 3.0 mlof dry THF under N₂. The reaction was run in an ultrasonic bath at atemperature range of 24-30° C. To the well-agitated mixture was addeddropwise 40 μl of 1,2-dibromoethane/N₂. The reaction was allowed toproceed for 1 to 11/2 hours at 28° C./N₂. The concentration of theGrignard reagent was 4.0 mmoles in 10 ml of dry THF.

The steroid from Example 2, i.e. the pyridylthio ester, 205 mg, wassuspended in 2.0 ml of dry THF, cooled to -80° C. and the above preparedGrignard was added via syringe to the steroidal suspension in 5-10minutes/N₂. The reaction was allowed to proceed for 1 hour at -80° C./N₂and then at -10° C. for an additional hour/N₂. The solution was dilutedwith 10.0 ml of methylene chloride, and quenched with saturated aqueoussolution of NH₄ Cl to pH=4. The organic layers were separated, washed 3times with water; 3 times with saturated sodium chloride, dried overMgSO₄, filtered, and evaporated under vacuum to afford 105.0 mg of crudeproduct.

The crude product was chromatographed on TLC (one plate, 20 cm×20 cm×20cm×1000 μm silica gel) eluted with 80:20 (CH₂ Cl₂ -acetone) to afford66.0 mg of single spot material. Crystallization from EtOAc afforded45.0 mg of the above-titled compound, m.pt. 286-287° C.

FAB for C₂₆ H₃₃ NO₂ S (Calcd.) 424; Found 424.

Example 14

Synthesis of 17-β-(4-methylsulfinylbenzoyl) and-(4-methylsulfonylbenzoyl)-4-aza-5α-androst-1-en-3-one

A. Oxidation

19.91 mg of the methylthio product from Example 13 was dissolved in 2.5ml of CH₂ Cl₂, cooled to 0-(-2)° C. and was treated with a solution 9.6mg of m-chloroperbenzoic acid in 1.0 ml of CH₂ Cl₂ over a period of 4minutes. After stirring for 1 hour at 0-(-2)° C., the reaction wasdiluted with 10 ml. CH₂ Cl₂. The layers were washed subsequently with2.5% NaHCO₃, H₂ O and saturated NaCl solutions. The organic layer wasdried over MgSO₄ overnight, filtered and evaporated in vacuo to yield 17mg product. Crystallization from EtOAc gave 11.8 mg of the above-titledcompound, a solid, mp. 313-313.5° C. (with dec.).

Anal. Calcd. for C₂₆ H₃₃ NO₃ S.1/4H₂ O: C,70.31; H,7.60; N,3.15; Found:C,70.47; H,7.70; N,3.00. FAB for C₂₆ H₃₃ NO₃ S (Calcd. 440); Found 440.

Sulfone

Fifteen percent (15%) of the corresponding sulfone,17β-(4-methylsulfonyl benzoyl) derivative, was isolated bychromatography from the reaction as a byproduct. Recrystallized fromEtOAc to yield a solid, mp. 279-279.5° C. Molecular weight by FAB showed456; calculated 456.

Anal. for C₂₆ H₃₃ NO₄ S.0.25 H₂ O Calc: C,67.87; H,7.28; N,3.04. Found:C,67.96; H,6.72; N,2.95.

Example 15

Synthesis of17-β-(4-acetoxymethylthiobenzoyl)-4-aza-5α-androst-1-en-3-one

Trifluoroacetic anhydride (165 μl) was dissolved in 780 μl of aceticanhydride and kept for 5 hours at room temperature (RT).

To 300 μl of the above solution of mixed anhydrides was added 34.15 mgpure sulfoxide from Example 14 with stirring. A few minutes later 54.0μl of 2,6-lutidine was added and the reaction was allowed to stir atRT/N₂ for 17 hours.

The liquid anhydrides were removed under reduced pressure and theremaining residue extracted (4 times with CHCl₃). The CHCl₃ extractswere washed subsequently with dilute HCl; 5% NaHCO₃ solution, 3 times; 3times with H₂ O; and finally with saturated NaCl solution, and thendried over MgSO₄ filtered and evaporated the solution to dryness invacuo to yield 42.1 mg of crude product.

The crude product from Step A was purified by chromatography on silicagel using 95:5 (CHCl₃ -acetone) as eluant and then crystallizing theobtained solid from EtOAc to yield 17.8 mg of the above-titled compoundas crystals, m.pt. 235-236° C. (dec.).

Anal. Calcd. for C₂₈ H₃₅ O₄ NS.1/4 H₂ O: C,68.57; H,7.40; N,2.86; Found:C,69.02; H,7.39; N,2.73. FAB for C₂₈ H₂₈ O₄ NS calcd.: 482; Found 482.The NMR (proton) was in agreement with the assigned product structure.

Example 16

Synthesis of 17β(4-mercaptobenzoyl)-4-aza-5α-androst-1-en-3 one

40.0 mg of the acetoxy-methyl-thio derivative from Example 15 wassuspended in 3.0 ml of isopropanol. The reaction mixture was flushedseveral times with N₂, and with vacuum, and the system kept undernitrogen atmosphere. To the above mixture was added 40.0 mg of K₂ CO₃ in2.00 ml of water (free of oxygen) via syringe, and the temperature ofthe reaction mixture was allowed to rise to 80° C. under gentle refluxunder slight vacuum for 10 minutes, and then under N₂ for 1 hour. After1 hour, the reaction mixture was a clear yellow solution. It was broughtto R.T., cooled to 0-5° C. and quenched with 2.5 N HCl acid/N₂. Thereaction mixture was extracted 4 times with CH₂ Cl₂. The organic layerwas washed with H₂ O 4 times; 3 times with saturated salt solution, andfinally dried over MgSO₄. Filtered and evaporated to dryness in vacuo toyield 36.9 mg of crude product. The crude product was dissolved in 2.0ml of CHCl₃, filtered through Teflon (Acrodisc CR) and purified bypreparative HPLC on silica gel and eluted with 60:40 (CH₂ Cl₂ -acetone).Crystallization, from EtOAc afforded a single spot material, 20.7 mg ofthe above-titled compound, m.pt. 285-286° C.

Anal. Calcd. for C₂₅ H₃₁ O₂ NS.1/2 H₂ O: C,72.19; H,7.69; N,3.24; Found:C,71.82; H,7.43; N,3.26. FAB: Calcd. for C₂₅ H₃₁ O₂ NS: 410; Found: 410.

Example 17

Synthesis of 17-β-(4-Dimethylaminobenzoyl)-4-aza-5-α-androst-1-en-3-one

To a suspension of 291.0 mg of dry activated magnesium chips in 8.0 mlof dry THF was added 800.0 mg of 4-bromo-N,N-dimethylaniline in 2.0 mlof dry THF under N₂. The reaction was run in an ultrasonic bath at atemperature range of 24-30° C. To the well-agitated mixture was addeddropwise 30 μl of 1,2-dibromoethane/N₂. The reaction was allowed toproceed for 1 to 11/2 hours at 28° C./N₂. The concentration of theGrignard reagent was 4.0 mmoles in 10.0 ml of dry THF.

The steroid from Example 2 (205 mg of pyridyl thioester) was suspendedin 2.0 ml of dry THF, cooled to -80° C. and the above Grignard 3.8 ml (3equivalents) was added via syringe to the steroidal suspension over 5-10minutes/N₂. The reaction was allowed to proceed for 1 hour at -80° C./N₂and then at -10° C. for an additional hour/N₂. The solution was dilutedwith 10.0 ml of methylene chloride and quenched with a saturated aqueoussolution of NH₄ Cl to pH=4. The organic layers were separated, washed 3times with water 3 times with saturated sodium chloride, dried overMgSO₄, filtered, and evaporated under vacuum to afford 151.3 mg of crudeproduct. Crystallization from ethyl acetate gave 124.5 mg of theabove-titled compound, m.pt. 268.5-269° C.

FAB: Calcd. C₂₇ H₃₆ N₂ O₂ : 421; Found: 421. The NMR (proton in CDCl₃)confirmed the assigned structure.

Example 18

General Procedure for Preparing Protected Silyl Derivatives

1.0 mole of phenol or its derivatives, or 1 mole of alcohol is treatedwith 1.5 liters of dry methylene chloride. To the clear solution isadded dry 3.0 moles of imidazole/N₂. The clear solution is cooled to 0°C./N₂, and 2.0 moles of t-butyl dimethyl chlorosilane in 300.0 ml of drymethylene chloride is added dropwise at 0° C./N₂. Towards the end of theaddition, precipitation occurs. The ice bath is removed, and thereaction is allowed to proceed overnight at R.T./N₂. Filter, wash thecake with cold CH₂ Cl₂ solution, and the solvent is evaporated in vacuoto afford crude product. The crude product was readily purified byfiltering through a silica gel column. (1 gr. of crude product per 100 gof silica gel, using CH₂ Cl₂ as eluant) This method gives about 99% ofpure silyl derivatives of phenols and alcohols.

Example 19

Synthesis of 17-β-(4-Hydroxybenzoyl)-4-aza-5-α-androst-1-ene-3-one

A. Grignard Reaction

To a suspension of 1.22 g of dry activated magnesium chips in 20.0 ml ofdry THF was added 5.6 g of 1-bromo-4-(tertiary-butyl dimethylsilyloxy)benzene (prepared from p-bromophenol by the General Proceduredetailed above) in 10.0 ml of THF under N₂. The reaction was run in anultrasonic bath at a temperature range of 24-30° C. To the well-agitatedmixture was added dropwise 150 μl-200 μl of 1,2-dibromoethane/N₂. Thereaction was allowed to proceed for 1-11/2 hours at 28° C./N₂. Theconcentration of the Grignard reagent formed was 19.5 mmoles in 30.0 mlof dry THF.

The steroid from Example 2 (1.02 g, 2.49 mmoles) was suspended in 20.0ml of dry THF, cooled to -80° C. and the above-prepared Grignard (11.5ml) was added via syringe to the steroidal suspension in 5-10minutes/N₂. The reaction was allowed to proceed for 1 hour at -80°C./N₂, and then at -10° C. for an additional hour/N₂. The reactionsolution was diluted with 10.0 ml of methylene chloride and quenchedwith a saturated aqueous solution of NH₄ Cl to pH=4. Organic layers wereseparated, washed 3 times with H₂ O, 3 times with saturated sodiumchloride, dried over MgSO₄, filtered, and evaporated under a vacuum to ayellow color solid. Crystallization from ethyl acetate afforded 607 mgof product m.p. 248-249° C.

Anal. Calcd. for C₃₁ H₄₅ O₃ NSi: C,73.32; H,8.93; N,2.75 Found: C,73.27;H,8.99; N,2.75. FAB: Found 508; Calc. 508.

B. Desilylation

Dissolved 1.3 g of product from above step A in 20.0 ml of dry THF.Cooled to -5° C. and added 437 μl of glacial acetic acid/N₂. To the coldsolution at -5° C. was added via syringe 3.0 ml tetra-n-butylammoniumfluoride dropwise under N₂ atmosphere. Allowed the reaction to proceedunder stirring for 11/2-2 hours at 0° to -5° C./N₂. The reaction mixturewas poured into a 2-layer mixture of ethyl acetate/sodium bicarbonatesaturated solution at 0° C. The water layer was separated and furtherextracted with EtOAc 3 times and with CH₂ Cl₂ (3 times).

The organic layers were combined, washed 3 times with H₂ O, 1 time withsaturated sodium chloride solution, and dried over MgSO₄, filtered andevaporated to dryness under vacuum. The crude product was crystallizedfrom ethyl acetate to afford 977.9 mg, and further recrystallized frommethanol to afford 842.3 mg of the above-titled product, m.pt. 296-297°C.

Anal. Calcd. for C₂₅ H₃₁ NO₃.1/3 H₂ O: C,75.15; H,7.98; N,3.51. Found:C,75.13; H,7.76; N,3.54. (Mass Spec.) FAB: Found 394; Calcd. 394.

Example 20

17-β-(3,5-dimethyl-4-hydroxybenzoyl)-4-aza-5α-androst-1-ene-3-on

A. Preparation of Grignard Reagent

To a suspension of 260.0 mg of dry activated magnesium chips in 6.0 mlof dry THF was added 628.0 mg of1-bromo-3,5-dimethyl-4-tertiary-butyl-dimethylsilyloxybenzene (preparedfrom 4-bromo-2,6-dimethylphenol by the General Procedure describedabove) in 4.0 ml of THF/N₂. The reaction was conducted in an ultrasonicbath at a temperature range of 24° C.-30° C. To the well-agitatedmixture was added dropwise 40 μl of 1,2-dibromoethane/N₂. The reactionwas allowed to proceed for 2 hours/N₂. The concentration of the Grignardreagent thus formed was 2 mmoles in 10.0 ml of dry THF.

The steroid from Example 2 (205.0 mg (0.5 mmoles) was suspended in 3.0ml of dry THF, cooled to -80° C., and 7.5 ml (1.50 millieq.) of theabove-prepared Grignard was introduced via syringe to the steroidalsuspension over a period of 5-10 minutes/N₂. The reaction was allowed toproceed for 1 hour at -80° C./N₂ and then at -10° C. for additionalhour/N₂.

The reaction was quenched with 1N HCl, and then diluted with chloroform.The organic layers were combined, washed 3 times with H₂ O, 3 times withsaturated sodium chloride and dried over MgSO₄, filtered andconcentrated in vacuo. The crude residue was washed with ether to afford121.7 mg of product.

The crude product was dissolved in 70:30 (CHCl₃ -acetone), filteredthrough Teflon (Acrodisc CR) and purified by preparative HPLC (WatersPrep-pak) on silica gel and eluted with 70:30 (CHCl₃ -acetone).

The major component was recrystallized from ethyl acetate to give 52.0mg of product m.pt 245-245.5° C.

Anal. Calcd. for C₃₃ H₄₉ O₃ NSi: C,73.96; H,9.23; N,2.61; Found:C,74.06; H,9.33: N,2.64; (Mass Spec.) FAB: Found: 536; Calc.: 536

B. Deblocking the Silyl Derivative

Dissolved 54.0 mg of the above product from A in dry THF (1.3 ml). Theclear solution was cooled to 0° C., and 29 μl of glacial HOAc was addedvia syringe/N₂. To the above solution was added dropwise 172 μl oftetra-n-butylammonium fluoride at 0° C. dropwise via syringe/N₂. Allowedthe reaction to proceed at 0° C./N₂ for 11/2 hours. The reaction mixturewas poured into ice/saturated NaHCO₃ solution and EtOAc. Stirred forseveral minutes. Allow the layers to separate, and the H₂ O layer wasextracted 3 times with EtOAc and 3 times with CHCl₃.

Combined the organic layers and washed 3 times with H₂ O, then 3 timeswith saturated NaCl, and then dried over MgSO₄, filtered and evaporatedto dryness in vacuum to afford 52.2 mg.

The product was crystallized from EtOAc to give 22.5 mg of theabove-titled product m.pt 305-306° C.

Calc. for C₂₇ H₃₅ O₃ N.H₂ O: C, 73.77; H, 8.49; N, 3.10. Found: C,73.62; H, 7.90; N, 3.44. (Mass Spec.) FAB: Calc: 422; Found: 422

Example 21

Synthesis of 17-β-(4-Methoxybenzoyl)-4-aza-5-α-androst-1-ene-3-one

A. Grignard Reaction

To a suspension of 258.0 mg of dry activated Mg chips in 8.0 ml ofTHF/N₂ was added 748.0 mg p-bromoanisole in 2.0 ml of dry THF. Thereaction was run in an ultrasonic bath at a temperature range of 24-30°C./N₂. To the well-agitated mixture was added dropwise 30.0 μl of1,2-dibromoethane as a catalyst. The reaction was allowed to progressfor 1-2 hours at 28° C. The formed Grignard reagent had a concentrationof 4 mmoles in 10.0 μl of dry THF.

The steroid from Example 2 (205.0 mg (0.50 mml) was suspended in 2.0 mlof THF, cooled to -78° C. and the above-prepared Grignard reagent (3.75ml; 14 milliequivalents) was added via syringe to the steroidalsuspension over 5-10 minutes/N₂ and then at -10° C. for an additionalhour/N₂. The resulting reaction mixture was a clear solution, which wascooled to 0-5° C., diluted with chloroform and quenched with 1N HClacid. The organic layers were separated, washed with H₂ O 2 times,followed with saturated NaCl solution, dried over MgSO₄, filtered andevaporated in vacuo. The crude product was washed with ether, andcrystallized from EtOAc to give 110 mg of product m.pt 305-306° C.

Further purification was carried out by chromatographic isolation on aTLC. plate, (20 cm×20 cm×1000 μm), using as eluant, 70:30 (CHCl₃ :acetone). Recrystallization from EtOAc yielded 78.56 mg of theabove-titled product, m.pt 305-306° C. (dec.).

(Mass Spec) FAB: Calcd.,408; Found 408.

Example 22

Synthesis of 17-β-(3-hydroxybenzoyl)-4-aza-5α-androst-1-ene-3 one

A. Preparation of Grignard Reagent

To a suspension of 230.0 mg of dry activated Mg chips in 2.0 ml of dryTHF was added 722.4 mg of 1-bromo-3-tertiary-butyldimethyl-silyloxybenzene (prepared from 3-bromophenol by the GeneralProcedure described above) in 8.0 ml of dry THF/N₂. The reaction was runin an ultrasonic bath at a temperature range of 24-30° C./N₂. To thewell-agitated mixture was added dropwise 20.0 μl of1,2-dibromoethane/N₂. Allowed the reaction to progress for 21/2 hours at28° C./N₂. The formed Grignard reagent had a concentration of 2.52mmoles in 10.0 ml of dry THF.

The steroid from Example 2 (205.0 mg (0.5 mmoles) was suspended in 2.0ml of THF, cooled to -78° C. and the above-prepared Grignard reagent(6.0 ml, (1.5 milliequivalents) was added via syringe to the steroidalsuspension over 5-10 minutes/N₂, and then stirred for an additional hourat -10° C./N₂. The clear reaction mixture was quenched at 0 to -5° C.with 1N HCl acid for 10.0 minutes and diluted with CHCl₃. The combinedorganic layers were washed 3 times with H₂ O, 3 times with saturatedNaCl, and then dried over MgSO₄, filtered and concentrated in vacuo toafford crude product. The product was purified on silica gel column andwas eluted with 70:30 (CHCl₃ -acetone). The desired product amounted to58.0 mg, as the silyl derivative,17β-(3-tertiary-butyldimethylsilyloxybenzoyl)-4-methyl-4-aza-5α-androst-1-en-3-one.

B. Deblocking

57.6 mg of the above silyl derivative was dissolved in 3.0 ml of dryTHF. The solution was cooled to 0° C., and 20 μl of glacial acetic acidwas introduced via syringe. To the clear solution was added 130.0 μl of(n-butyl)₄ NF via syringe, and allowed the reaction to proceed for 1hour/N₂ at 0° C. The reaction mixture was poured into EtOAc/NaHCO₃ sat.solution @ 0° C. The water layer was separated, extracted 3 times withEtOAc and then 3 times with chloroform. The organic layers were combinedand washed 3 times with H₂ O, 3 times with saturated NaCl solution,dried over MgSO₄, filtered and evaporated in vacuo to give 57.11 mg ofcrude product. The crude product was chromatographed by TLC (one plate,20 cm×20 cm×250 μm silica gel), eluted with 70:30 (CHCl₃ -acetone) toafford 44.5 mg of the above-titled product. Recrystallization from EtOAcgave 29.30 mg m.pt 279-280° C.

Anal. Calcl. for C₂₅ H₃₁ NO₃ : 8H₂ O: C,73.60; H,8.06; N,3.43. Found:C,73.26; H,8.22; N,3.28. (Mass Spec.) FAB: Calcd: 394; Found 394.

Example 23

Synthesis of 17-β-(4-hydroxymethyl-benzoyl)-4-aza-5α-androst-1-en-3-one

A. Preparation of Grignard solution

To a suspension of 100.0 mg (4 mmoles) of dry activated Mg chips in 5.0ml of dry THF/N₂, was added 753.0 mg (2.5 moles) of1-bromo-4-tertiary-butyl dimethyl silyloxy methyl benzene (prepared from4-bromobenzyl alcohol by the General Procedure described above). Thereaction was conducted in an ultrasonic bath at a temperature range of24-30° C./N₂. To the well-agitated mixture was added 20 μl of1,2-dibromoethane/N₂. Allowed the reaction to progress for 2 hours at28° C./N₂. The concentration of formed Grignard was 2.5 mmoles in 5.0 mlof dry THF.

B. Grignard Reaction

The steroid from Example 2 (205.0 mg (0.5 mmoles) was suspended in 2.0ml of THF, cooled to -78° C., and the above-prepared Grignard (3.0 ml,3.75 milliequivalents) was introduced via syringe into the steroidalsuspension over 5-10 minutes/N₂. Allowed the reaction to progress for 1hour at -80° C./N₂, and then for an additional hour at -10° C./N₂. Theclear reaction solution was quenched with saturated NH₄ Cl at 0° to -5°C., and then diluted with CH₂ Cl₂. The organic layers were separated andwashed 3 times with water, 3 times with saturated NaCl, dried overMgSO₄, filtered and evaporated in vacuo to dryness. Crude product wascrystallized from EtOAc to give 137.8 mg of silyl product.

(Mass Spec.) FAB: Calcd for C₃₀ H₄₁ O₃ NSi: 521.75 Found: 522.0.

C. Deblocking of Silyl Derivative

The product from Step B above (23.67 mg) was dissolved in 0.5 ml of THFand 0.5 ml of MeOH and cooled to 0° C./N₂. To the cold solution wasadded 10 μl of concentrated sulfuric acid (98%). The reaction wasstirred for 45 minutes at 0° C./N₂. To the cold solution at 0° C. wasslowly added a saturated solution of NaHCO₃ and chloroform. Extracted 3times with CHCl₃. The organic layers were washed 3 times with water, 3times with saturated NaCl, solution dried over MgSO₄, filtered andevaporated to dryness in vacuo, to afford 10.18 mg. After chromatographyon a TLC plate (elution with 1:1 CHCl₂ : acetone) The crude product wascrystallized from EtOAc to give 6.0 mg of the above-titled product, m.pt318-320° C.

Anal. Calcd. for C₂₆ H₃₃ O₃ N.1/3H₂ O: C,75.41: H,7.94; N,3.38. Found:C,75.61; H,7.84; N,3.12. (Mass Spec.) FAB: Calc.: 408; Found: 408

Example 24

Synthesis of 17-β-(4-Carboxybenzoyl)-4-aza-5α-androst-1-en-3-one

A. Oxidation

90.2 mg of the product from Example 23 was dissolved in 2.63 ml ofglacial acetic acid and to the clear solution was added 69.0 mg of CrO₃(previously dried over P₂ O₅ at R.T. for 2 days in vacuo). Afterstirring overnight, the reaction mixture was diluted with water andallowed to age overnight in the refrigerator. The reaction mixture wasfiltered and the mother liquor and washes were extracted overnight usinga liquid-liquid extractor, (H₂ O-EtOAc) under reflux conditions. Theorganic layer was dried over MgSO₄, filtered and evaporated in vacuo.The residue was dissolved in hot MeOH, filtered and evaporated in vacuoto afford a product weighing 32.0 mg.

FAB: Calc. for C₂₆ H₃₁ O₄ N: 422.0; Found: 422.

B. Purification

The above free acid was purified by dissolving the above product in 1Nsodium hydroxide solution. The clear solution was extracted 3 times withEtOAc. The aqueous basic solution was cooled and acidified with 1N HClacid dropwise to pH=4 with stirring. The reaction mixture was allowed toage for 1 hour at 0° C. It was. filtered and the residue was washed withcold water. Dried overnight to 100° C. in vacuum <0.2 mm pressure.

Yield of the above-titled free acid was 9.85 mg. FAB: Calc. for C₂₅ H₃₁O₄ N: 422; Found 422. NMR analysis indicated the product to be an acid.

C. Sodium Salt of Above Acid

4.9 mg of the above product acid B was dissolved in 2.0 ml of hotmethanol. To the clear solution, was added 11.6 μl of 1N NaOH(aq). Tosolution after methanol evaporation in vacuo, was added water to reachpH 7.21. The aqueous solution was freeze dried to give 6.3 mg of thesodium salt of the above-titled product.

Example 25

Synthesis of 17-β-(4-hydroxyethylbenzoyl)-4-aza-5α-androst-1-en-3-one

A. Grignard Reagent

To a suspension of 252 mg of dry activated Mg chips in 10.0 ml of dryTHF was added 1.26 g (4 mmoles) of 1-bromo-4 tertiary-butyl dimethylsilyloxy ethyl benzene (prepared from 2-(p-bromophenyl) ethanol by theGeneral Procedure described above). The reaction mixture was vigorouslystirred using an ultrasonic vibrator/N₂. To the well-agitated mixturewas added 40 μl of 1,2-dibromoethane to catalyze the above reaction.Allowed the reaction to progress for 31/2-4 hours/N₂. The concentrationof formed Grignard reagent was 4 mmoles in 10 ml of THF.

B. Grignard Reaction

205.0 mg (0.5 mmoles) of the aza-steroid of Example 2 was suspended in2.0 ml of dry THF/N₂, cooled to -80° C., and the above-prepared Grignard(3.75 ml, 1.5 milliequivalents) via syringe was introduced into thesteroidal suspension over 5-10 minutes/N₂. The reaction was run at -80°C. for 1 hour/N₂ and then for an additional hour at -10° C. The reactionwas quenched with a saturated solution of NH₄ Cl at 0-5° C. and dilutedwith 10.0 ml of CH₂ Cl₂. The organic layers were washed with water (3times), saturated NaCl solution (3 times), dried with MgSO₄, filteredand evaporated in vacuo to dryness. The crude product was crystallizedfrom EtOAc overnight to give 152.0 mg of product m.pt. 233-234° C.

Anal. Calcd. for C₃₃ H₄₉ O₃ NSi:1/4 H₂ O: C,73.55; H,9.18, N,2.59.Found: C,73.45; H,8.94; N,3.21 FAB: Calc. 536; Found: 536

C. Desilylation

70.8 mg of product from Step B, was dissolved in 1.45 ml of methanol and1.45 ml of THF. The solution was cooled to 0-5° C. and 29 μl of conc. H₂SO₄ was added via syringe under N₂. The reaction was allowed to proceedfor 45 minutes/N₂. The reaction was carefully quenched at 0° C. with asaturated solution of NaHCO₃, and extracted 3 times with CH₂ Cl₂. Theorganic layers were separated, washed with water (3 times), then withsaturated NaCl solution, dried over MgSO₄, filtered and evaporated invacuo to give 43.0 mg of crude product. The crude product was placed ona column of silica gel and was eluted with 1:1 acetone-CH₂ Cl₂. Theisolated product was crystallized from anhydrous methanol to afford 20.0mg of the above-titled product m.pt 292-293° C. with dec.

Anal. Calcd. for C₂₇ H₃₅ O₃ N.1/4 H₂ : C,75.31; H,8.25; N,3.25. Found:C,75.49; H,8.29; N,3.45. FAB: Calcd 422; Found 422.

Example 26

Synthesis of 17-β-(4-carboxymethylbenzoyl)-4-aza-5α-androst-1-en-3-one

A. Oxidation

13.0 mg of the product from Example 25 was dissolved in 1 ml of glacialacetic acid. To the clear solution was added 10.0 mg of CrO₃ (previouslydried over P₂ O₅ in vacuum at R.T.). Allowed the reaction to progressovernight at R.T., and then at 0° C. for 48 hours. The addition of 7.0ml of water caused the product to crystallize overnight in arefrigerator. The crude product was isolated, washed with cold water anddried in a vacuum at 110° C. below 1 mm pressure.

The dried crude product was dissolved in IN sodium hydroxide and thebasic solution was extracted 3 times with methylene chloride (Theorganic layers were separated, and the aqueous basic solution was cooledand acidified with 1.5 N hydrochloric acid. The precipitate wasfiltered, washed with water dried at 110° C. under vacuum at 0.1 mmpressure.

Yield of above-titled product=7.0 mg. FAB Calc. C₂₇ H₃₃ O₄ N: 436; Found436.

Example 27

Synthesis of 17-β-(3,4-dihydroxybenzoyl)-4-aza-5α-androst-1-en-3-one

A. Grignard

To a suspension of 258.5 mg of dry activated magnesium chips in 10.0 mlof dry THF, was added 482 mg. of 4-bromo-1,2-methylenedioxybenzene/N₂.(The starting material is commercially available from Aldrich Chemical)The reaction was conducted in an ultrasonic water bath at a temperaturerange of 24°-30° C. To the well-agitated mixture was added 40 μl of1,2-dibromoethane as a catalyst/N₂, and the reaction was allowed toprogress for 11/2-2 hours at 28° C./N₂. The concentration of the formedGrignard reagent was 3.75 mmoles in 10 ml of dry THF.

The steroid from Example 2 (410 mg, 1 mmole) was suspended in 4.0 ml ofdry THF/N₂ and cooled to -80° C. and 8.0 ml of the above-preparedGrignard (3.04 milliequivalents) was added via syringe to the steroidalsuspension/N₂ over a period of 5-10 minutes. The reaction was allowed toproceed for 1 hour at -80° C., and then at -10° C. for an additionalhour/N₂. The reaction mixture was diluted with CH₂ Cl₂, and thenquenched with 1N HCl at -5° C.

The organic layers were collected and washed with water 3 times,saturated NaCl solution 3 times, dried over MgSO₄, filtered andevaporated in vacuo to dryness. Purification of the crude product wascarried out on 50.0 g of silica gel using as eluant 1:1(CH₂ Cl₂-acetone) to give 347.0 mg. FAB showed 422; Calcd. 422.

62.4 mg of the above product was crystallized from EtOAc to afford 11.39mg of product m.pt.324-325° C.

Anal. Calcd. for C₂₆ H₃₁ O₄ N.3/4 H₂ O: C,71.78; H,7.53; N,3.22. Found:C,71.90; H,7.54; N,3.25. FAB for C₂₆ H₃₁ O₄ N showed 422; Calcd: 422.

B. Cleavage of Methylene Dioxylan Group

70.0 mg of the product from Step A was dissolved in dry 25.0 ml of1,2-dichloroethane at R.T./N₂. The solution was allowed to cool to -10°C., and 1.03 ml of BBr₃ (1.0 M solution in dichloromethane) was addeddropwise under N₂ atmosphere. The reaction was allowed to proceed atR.T. for 31/2-4 hours/N₂. After 4 hours/N₂, the reaction was cooled to(-10° C.) and quenched with 10.0 ml of methanol for 10 minutes at 0° C.,and then gradually the temperature was allowed to rise to R.T./N₂. Thereaction mixture was evaporated in vacuo to dryness. The residue wasextracted 3 times with EtOAc. The organic layers were washed with water3 times, 2 times with saturated NaHCO₃ solution, 3 times with water andfinally with a saturated solution of NaCl. The organic layers were driedover magnesium sulfate, filtered and concentrated in vacuo. The crudematerial was chromatographed on 2 silica gel plates, (20 cm×20 cm×20cm×250 μm) eluted with 1:1 (acetone-methylene chloride).Recrystallization from EtOAc afforded 5.0 mg of the above-titled productm.p. 222-222.5° C.

Anal. Calcd. for C₂₅ H₃₁ O₄ N.1/2 H₂ O: C,71.78; H,7.66; N,3.35. Found:C,71.71; E,7.71; N,3.33. FAB: Calcd. for C₂₅ H₃₁ O₄ N: 410; Found 410.

Example 28

Synthesis of 17-β-(2 methoxybenzoyl)-4-aza-5α-androst-1-ene-3-one

A. Grignard

To a suspension of 258.0 mg of dry activated magnesium chips in 8.0 mlof dry THF was added 771.0 mg of o-bromoanisole in 2.0 ml of dry THF/N₂.The reaction was conducted in an ultrasonic water bath at a temperaturerange of 24-30° C. To the well-agitated mixture was added 30 μl of1,2-dibromoethane/N₂, and the reaction was allowed to progress for 2hours at 28° C./N₂. The concentration of the formed Grignard reagent was4 mmoles in 10.0 ml of dry THF.

The steroid from Example 2 (205 mg, 0.5 mmoles) was suspended in 2.0 mlof dry THF/N₂, cooled to -79° C., and 4.0 ml of the above-preparedGrignard (1.6 milli-equivalents) was added via syringe to the steroidalsuspension/N₂ over a period of 5-10 minutes. The reaction mixture wasallowed to proceed for 1 hour at -80° C., and then at 0-2° C. for anadditional hour/N₂. The reaction mixture was diluted with CH₂ Cl₂ andthen quenched with 1N HCl solution at 0° C.

The organic layers were combined, washed 3 times with water, 3 timeswith saturated NaCl solution; and dried over MgSO₄. Filtered andevaporated in vacuum to dryness. The crude material was crystallizedfrom EtOAc to give 124.5 mg of product m.pt 228-230° C. Purification onsilica gel column using 70:30 (CHCl₃ -acetone) gave a single spotmaterial in a yield of 83.0 mg m.pt. 241-241.5.

Anal. Calcd. for C₂₆ H₃₃ O₃ N: C,76.91; H,8.19; N,3.45 Found: C,76.36;H,8.26; N,3.35. FAB calcd. for C₂₆ H₃₃ O₃ N: 406; Found: 406.

B. Cleavage of Methoxy Group

12.7 mg (0.03 mmoles) of the product from Step A was dissolved in 5.0 mlof dry methylene chloride/N₂. To clear solution at -79° C./N, was added50 μl of 1 mmole/ml of BBr₃ in CH₂ Cl₂ via syringe dropwise. Allowed thereaction to proceed at R.T. overnight/N₂ with rapid stirring. Next day,a clear yellow solution was obtained. The reaction mixture was cooled to0-2° C. and quenched with water, to hydrolyze excess of BBr₃. Theorganic phase was washed 3 times with dilute sodium hydroxide, 3 timeswith water, 3 times with dilute HCl, 3 times with water, 3 times withsaturated NaCl solution, and dried the organic layer over MgSO₄.Filtered, concentrated in a vacuum to dryness. The crude productcrystallized from EtOAc to afford 7.0 mg of a pure single spot materialbeing 17-β-(2-hydroxymethyl-benzoyl)-4-aza-5-α-androst-1-en-3-one.

FAB for C₂₅ H₃₁ NO₂ ; Calcd: 394; Found: 394.

Example 29

17β(α-hydroxybenzyl)-4-aza-5α-androst-1-ene-3-one

570 milligrams of 17β-benzoyl-4-aza-5α-androst-1-ene-3-one (preparedfrom the thiopyridyl ester of Example 2 and commercially availablephenyl magnesium bromide, analogously via the procedure in Example 5, toproduce the 17-benzoyl derivative, mp. 295-296° C. crystallized fromEtOAc) was suspended in 80 ml of anhydrous isopropanol. To thesuspension was added 500.0 mg of NaBH₄ in 5 portions. When all thehydride was added, 20.0 ml of dry THF was carefully added, so that thereaction mixture became a clear solution. Allowed the reaction toproceed at R.T./N₂ overnight. The reaction was quenched carefully with1N HCl, and allowed to stir under N₂ for an additional hour at R.T. Itwas then diluted with water, and extracted 3 times with CHCl₃. Theorganic layers were combined, washed 3 times with H₂ O; 3 times withsaturated NaCl solution, and dried over MgSO₄. Filtered and evaporatedto a white solid weighing 495.0 mg.

The crude material was crystallized from EtOAc to afford 349.5 mg ofmaterial. Further purification on a silica gel column, using as eluant,70:30 (CHCl₃ -acetone) gave a single spot material, 221 mg, of theabove-titled compound, m.pt 296-297° C.

Anal. Calcd. for C₂₅ H₃₃ NO₂ : C,79.17; H,8.78; N,3.70. Found: C,79.24;H,8.85; N,3.48. FAB Calcd. for C₂₅ H₃₃ NO₂ : 380; Found: 380.

Example 30

17β-hydroxymethyl-4aza-5α-androst-1-ene-3-one

500.0 mg of S-2-pyridyl-3-oxo-4-aza-5α-androst-1-ene-3 one (Example 2)was dissolved in 40.0 ml of dry THF at R.T./N₂. The solution was cooledto -78° C./N₂ and 5.5 ml of 1 M dibutyl aluminium hydride in THF wasslowly added via syringe to the solution, with rapid stirring. Allowedthe reaction to proceed at -76 to -78° C. for half an hour under N₂. Thetemperature was gradually brought to R.T. and the reaction mixture keptfor 2-1/2 hours/N₂. The reaction was then quenched at 0° to 5° C. with2N HCl acid, and then diluted with CHCl₃. The organic layers wereseparated, washed with H₂ O 3 times, then with saturated NaCl solution,and finally dried over MgSO₂. Filtered, and the organic phase wasevaporated under vacuum to give 216.0 mg of crude product.

The crude product was chromatographed on 20.0 g of E.M. silica gelcolumn, using 70:30(CHCl₃ -acetone) as eluant.

Yield of single spot material was 126.3 mg of the above-titled compound,m.pt. 271-271.5° C.

Calcd. for C₁₉ H₂₉ O₂ N: FAB 304; Found 304. NMR in CDCl₃ confirmed theabove structure.

Example 31

17β-Formyl-4-aza-5α-androst-1-ene-3-one

Into a 100.0 ml dry flask was placed 1.3 ml of oxalyl chloride (2 M inCH₂ Cl₂) with 50.0 ml of dry CH₂ Cl₂ /N₂. The above solution was cooledto -78° C. and 338 μl of DMSO was added dropwise via syringe/N₂. Themixture was stirred at -78° C./N₂ for 30 minutes, and a solution ofabove-prepared alcohol from Example 15, i.e. 17βhydroxymethyl-4-aza-5α-androst-1-ene-3-one (256.9 mg in 15.0 ml of dryCH₂ Cl₂ /N₂ was added via syringe. The reaction was allowed to progressfor one hour at -78° C./N₂. After an hour at -78° C., was added 1 ml ofdry triethylamine at a rapid rate. Reaction was raised slowly to R.T./N₂with stirring, the resulting yellow solution was then poured into 50.0ml of cold water. The organic layers were washed with a saturatedsolution of NaHCO₃, and then with a saturated solution of NaCl. Driedover MgSO₄, evaporated the solvent under vacuum to give 172.4 mg ofcrude product. The crude product was chromatographed on 60.0 g silicagel column using 70.30 (CHCl₃ -acetone), to give a single spot material.Crystallization from EtOAc afforded the above-titled compound, 37.7 mg,m.pt. 258-259° C.

Example 32

Synthesis of diastereoisomeric17β(α-hydroxybenzyl)-4-aza-5α-androst-1-ene-3-ones

26.3 of above-prepared formyl derivative from Example 31) was dissolvedin 7.0 ml of dry THF/N₂. The solution was cooled to -78° C./N₂, and 131μl of phenyl magnesium bromide (Aldrich reagent) 0.393 milliequivalents)in dry THF was added dropwise via syringe/N₂. Allowed the reaction toproceed for 1 hour/N₂ at -78° C. and then at R.T. for addition hour/N₂.

The reaction was quenched at 0-5° C. with 2.5N HCl, and then dilutedwith CHCl₃. Organic layers were separated, washed 3 times with water; 3times with saturated NaCl solution, dried over MgSO₄. Filtered andevaporated in vacuum to dryness to afford 28.6 mg of crude product.Analysis of the NMR spectra and peak heights from HPLC indicated thisproduct to be a 1:1 mixture of diastereoisomers. The crude product wasfiltered through a 1 μm Teflon filter and purified by HPLC on a WhitmanPortisil 10 column using 70:30(CHCl₃ -acetone). The FAB mass spectrumindicated the same M⁺ +1 for both isomers, being 380 mass units. Thefaster eluting isomer, m.pt. 289-289.5° C., was crystallized from EtOAcand showed a single spot material on TLC.

Anal. Calcd. for C₂₅ H₃₃ NO₂.1/4 H₂ O; C,78.39; H,8.81; N,3.65. Found:C,78.11; H,8.65; N,3.58.

The slower eluting isomer, m.pt. 300-301° C. showed a single spotmaterial on TLC. The faster isomer showed by NMR(CDCl₃): CH₃ at C-18 wasdeshielded (0.89δ) as compared to the slower isomer CH₃ at C-18 at(0.69δ). The benzilic proton for the faster isomer was also deshielded(4.5δ) versus (4.95δ). The olefinic proton at C-1 showed deshieldingeffects for the faster isomer at (6.81δ) to (6.62δ). From the abovedata, the two isomers showed distinctly different physical properties.

CHAPTER 3 Example 1

Preparation of 4-(2-(11-carboxyundecanoylamino)-phenoxy)butyric acid

Step A: Ethyl 4-(2-nitrophenoxy)butyrate(3)

To a stirred solution of 2-nitrophenol (1.4 g, 10 mM) and ethyl4-brombbutyrate (2.1 g, 1.57 mL, 11 mM) in 35 mL of dry acetone is added2 g (14.5 mM) of anhydrous, ground potassium carbonate. The resultantcolored mixture is then heated under a nitrogen atmosphere at gentlereflux until the color due to the phenol anion has dissipated and ayellow mixture remains. Concentration of the cooled and filtered mixtureyields an oil which on flash chromatography (silica gel, ethylacetate/hexane or methylene chloride as eluant) yields 2.4 g (96% yield)of the title compound (3) as an oily liquid. When substitutedortho-nitrophenols are used in place of 2-nitrophenol in the aboveexample, the corresponding substituted 2-nitrophenoxybutyrate isobtained. Likewise, when ethyl 4-bromobutyrate is replaced by other haloesters the corresponding 2-nitrophenoxyalkanoate is obtained.

Step B: Ethyl 4-(2-aminophenoxy)butyrate (4)

A solution of 3 (1.27 g, 5.0 mM) in 15 mL ethyl acetate containing 200mg of 5% palladium on carbon is reacted in a hydrogen atmosphere (40psig.) at room temperature until hydrogen uptake ceases. The mixture isthen filtered and concentrated in vacuo to yield 1.0+g of (4) as anoil/low melting solid.

Step C: 12-(Isopropylthio)dodecanoic acid (6)

A mixture of 12-bromododecanoic acid (5) (0.558 g, 2.0 mM) and sodiumisopropylthiolate (1.1 g, 11.2 mM) in 1,2-dimethoxyethane (50 mL) wasdeaerated (N₂), heated to 85° C. (bath temperature), and kept at thistemperature for 72 hours. The cooled mixture was filtered, the collectedsolid dissolved in water and filtered. The stirred solution wasacidified with dilute hydrochloric acid, aged, filtered, the solidwashed well with water and dried. There was obtained product 6 (0.54 g)as a white solid.

When other halo-acids are used in place of 12-bromododecanoic acid inthe above example, the corresponding (isopropylthio)-acid is obtained.

Likewise, when other mercaptan salts are used in place of sodiumisopropylthiolate in the above example, the corresponding(alkylthio)alkanoic acids are obtained.

Representative of, but not limited to, the acids obtained by thisprocedure are:

8-(Isopropylthio)octanoic acid

10-(Isopropylthio)decanoic acid

10-(Ethylthio)decanoic acid

11-(t-Butylthio)undecanoic acid

14-(n-Propylthio)tetradecanoic acid

9-(Methylthio)nonanoic acid

Step D: Ethyl 4-(2-(12-(Isopropylthio)dodecanoylamino)-phenoxy)-butyrate(7)

To a solution of (4) (0.25 g, 1.14 mM) and (6) (0.274 g, 1.0 mM) in drymethylene chloride (10 mL) at room temperature was added4-dimethylaminopyridine (0.122 g, 1.0 mM) followed within one minute bya solution of N,N'-dicyclohexylcarbodiimide (0.22 g, 1.06 mM) inmethylene chloride (1 mL), 3×1 mL rinses with methylene chloride. After2 days, the filtered mixture was concentrated in vacuo and the residueflash chromatographed on silica gel using 15-20% ethyl acetate in hexaneas eluant to give product 7 (0.22 g) as an oil that solidified readilyin a short time.

Step E 4-(2-(12-(Isopropylthio)dodecanoylamino)phenoxy)-butyric acid (8)

A stirred solution of ester (7) (0.124 g, 0.258 mM) in methanol (10 mL)was treated at room temperature under a nitrogen atmosphere with 2.5Nsodium hydroxide solution (0.6 mL). Methanol (2×2 mL) was used to clearthe mixture, and the reaction allowed to continue until TLC analysisshowed no ester remained. The filtered mixture was concentrated in vacuoand the residue obtained stirred with water (30 mL). After aging, themixture was filtered (The cake is the sodium salt of the product (100mg), and the stirred filtrate acidified with dilute hydrochloric acid,aged, filtered, washed with water and dried to give product 8 (0.02 g)as a white solid. M.P. 82-84° C., with softening from 66° C.

Treatment of 8 with NaIO₄ as in Step J_(a) will produce thecorresponding sulfoxide, and treatment of 8 with m-chloroperbenzoic acidwith Step J_(b) will produce the corresponding sulfone.

Step F: 4-(2-(12-(Isopropylthio)dodecanoylamino)phenoxy)-butyramide (9)

To a stirred solution of (7) (20 mg, 0.041 mM) in methanol (10 mL) isadded methanol saturated with ammonia (5 mL) and the stoppered mixtureallowed to stir at ambient temperatures until TLC analysis shows littleor no (D) remains. Concentration of the reaction mixture followed bypreparative thin layer chromatography (silica gel; 3% methanol/methylenechloride as eluant) yields product 9 (11 mg) as a waxy solid.

Step G: Ethyl 4-(2-Amino-phenylthio)butyrate (11)

To a stirred deaerated (N₂) solution of 2-aminothiophenol (10) (1.25 g.,10 mM) and ethyl 4-bromobutyrate (2.14 g., 11 mM) in 40 mL. of dry1,2-dimethoxyethane is added 8.3 g. of solid ground anhydrous potassiumcarbonate, the resultant mixture deaerated 3× under nitrogen and allowedto stir at room temperature until TLC analysis indicates the reaction iscomplete. The filtered mixture is then concentrated and the residueflash chromatographed on silica gel (85 g.) using 15% ethylacetate/hexane as eluant to give 1.8 g. of (11) as a pale tan oil.

Step H: Ethyl 4-(2-(10-(Isopropylthio)decanoylamino)-phenylthio)butyrate(12)

When (11) and 10-(Isopropylthio)decanoic are reacted togetheranalogously as per the conditions in Step (D) above, the title compound12 is obtained.

Step I: 4-(2-(10-(Isopropylthio)decanoylamino)phenylthio)-butyric acid(13)

When (12) is hydrolyzed as per the conditions of Step (E) the titlecompound 13 is obtained.

Step J: 4-(2-(11-(ethylsulfinyl)undecanoylamino)phenoxy)-butyric acid

When the subject esters or acids are treated with sodium metaperiodate(Step J_(a)) in a suitable solvent (e.g. acetone/water) thecorresponding sulfoxides are obtained. Treatment withmeta-chloroperbenzoic acid (Step J_(b)) yields the correspondingsulfones. For example, when ethyl4-(2-(11-(ethylthio)undecanoylamino)phenoxy)-butyrate 14 (0.045 g, 0.1mM) in acetone (10 mL) is reacted with sodium metaperiodate (0.072 g,0.33 mM) in water (2 mL) at room temperature the corresponding sulfoxide15 is obtained. Hydrolysis as per Step (E) yields product 16 as anoff-white solid. Additionally, treatment of 14 with m-chloroperbenzoicacid will produce the sulfone 17, which yields the acid 18 uponhydrolysis using the hydrolysis conditions of Step E.

The method of preparing the novel compounds of the present invention,already described above in general terms, may be further illustrated bythe following examples which should not be construed as beinglimitations on the scope or spirit of the instant invention.

Example 1

Synthesis of 4-(2-(11-Carboxyundecyloxy)phenoxy)-butyric acid (7)##STR67## A. Ethyl 4-(2-Benzyloxyphenoxy)-butyrate (3)

To a stirred solution of 2-benzyloxyphenol (1) (4.0 g, 20 nM) and ethyl4-bromobutyrate (2) (5.6 g, 28.7 mM) in dried acetone (100 mL) was addedanhydrous ground potassium carbonate (6.0 g, 44 mM) and the resultantmixture heated at reflux under nitrogen until TLC analysis showed theabsence of the starting phenol. Flash chromatography (silica gel, 15%ethyl acetate/hexane as eluant) of the filtered and concentrated mixtureyielded 3.0 g of product (3) as a clear oil.

When the ethyl 4-bromobutyrate is replaced by halo-esters in the aboveexample, the corresponding ether-ester is obtained. Likewise, when theabove phenol is replaced by other substituted 2-benzyloxyphenols, thecorresponding 2-substituted ethers are obtained. Substitution of a2-benzyloxy- or a 2-benzylthio-thiophenol for the 2-benzyloxyphenolyields the corresponding thioether-ester.

B. Ethyl 4-(2-Hydroxyphenoxy)-butyrate (4)

A mixture of (3) (1.57 g, 5.0 mM), ethanol (50 mL), glacial acetic acid(7 drops) and 10% palladium on carbon (0.7 g) was reacted in a hydrogenatmosphere (40 p.s.i.) at room temperature until hydrogen uptake ceased.Concentration of the filtered mixture yielded the product (4) as an oil.

C. Ethyl 4-(2-11-(Carbomethoxy)undecyloxyphenoxy)butyrate (6)

When (4) (0.224 g, 1.0 mM) and methyl 12-bromododecanoate (5) (0.32 g,1.1 mM) were reacted with potassium carbonate in acetone as per Example(A), there was obtained product 6 (0.3 g) as a colorless oil.

When methyl 12-bromododecanoate is replaced by other halo esters in theabove example, the corresponding diester is obtained.

D. 4-(2-(11-Carboxyundecyloxy)phenoxy)butyric acid (7)

To a stirred solution of (6) (0.102 g, 0.23 mM) in methanol (4 mL) andwater (3 drops) was added 2.5 N sodium hydroxide solution (0.55 mL, 1.37mM) dropwise, and the resultant mixture cleared with additional methanol(2 mL). When TLC analysis (2% methanol in methylene chloride (10 mL)containing glacial acetic acid (4 drops) indicated no mono- or diesterremained, the methanol was removed in vacuo, the residue stirred withwater (10 mL), and the solution filtered and acidified with 2Nhydrochloric acid. Filtration of the resultant precipitate followed bywashing with water and drying yielded product 7 (88 mg) as a whitesolid; M.P. collapses at 95° C., all melted at 105° C. (uncorr.; A.O.Spencer Hot Stage).

Calculated for C₂₂ H₃₄ O₆ : C. 66.98; H. 8.69. Found: C. 67.32; H. 8.45.

Compounds (1)-(7) all had NMR and Mass Spectral data consistant withtheir assigned molecular formulas.

4-(2-(11-Carboxyndecyloxy)phenylsulfinyl)butyric acid(7B)

When the subject thioethers, e.g., Compound 7A in Flow Sheet C, as theester or acid, are treated with sodium metaperoidate in a suitablesolvent (e.g., acetone/water) the corresponding sulfoxides are obtained.Likewise, reaction of the subject thioethers with m-chloroperbenzoicacid yields the corresponding sulfones. For example, when4-(2-(11-carboxyundecyloxy)phenylthio butyric acid 7A (0.41 g, 1.0 mM)in acetone (25 mM) is reacted with sodium metaperiodate (0.72 g, 3.3 mM)in water at room temperature, the title sulfoxide 7B is obtained. Whenthe same starting material in methylene chloride is reacted with excessm-chlorobenzoic acid, the corresponding sulfone is obtained.

Compounds (3)-(16) all had NMR and Mass Spectral data consistent withtheir assigned molecular structures.

Example 1

Preparation of 4-(2-(11-carboxyundecanoylamino)-phenoxy)butyric acid

Step A: Ethyl 4-(2-nitrophenoxy)butyrate (3)

To a stirred solution of 2-nitrophenol. (1) (1.4 g, 10 mM) and ethyl4-bromobutyrate (2.1 g, 1.57 mL, 11 mM) in 35 mL of dry acetone is added2 g (14.5 mM) of anhydrous, ground potassium carbonate. The resultantcolored mixture is then heated under a nitrogen atmosphere at gentlereflux until the color due to the phenol anion has dissipated and ayellow mixture remains. Concentration of the cooled and filtered mixtureyields an oil which on flash chromatography (silica gel, ethylacetate/hexane- or methylene chloride as eluant) yields 2.4 g (96%yield) of the title compound (3) as an oily liquid.

Step B: Ethyl 4-(2-aminophenoxy)butyrate (4)

A solution of (3) (1.27 g, 5.0 mM) in 15 mL ethyl acetate containing 200mg of 5% palladium on carbon is reacted in a hydrogen atmosphere (40psig.) at room temperature until hydrogen uptake ceases. The mixture isthen filtered and concentrated in vacuo to yield 1.0+g of (4) as anoil/low melting solid.

Step C: Dodecanedioic acid, mono methyl ester (6)

Diethyl dodecanedioate (5) (34.4 g, 0.12 M) is reacted with bariumhydroxide octahydrate (19.2 g, 0.06 M) in methanol (240 mL) as per theanalogous procedure of Org. Syn., Coll. Vol. III. p. 635 to yield 24.8 gof (6) as a white solid.

Step D: Dodecanedioic acid, mono methyl ester mono acid chloride (7)

A mixture of mono acid (6) (10.0 g, 0.041 M) and thionyl chloride (12.1mL, 0.166 M) is refluxed for 5 hours, the excess thionyl chlorideremoved in vacuo, and the residual acid chloride repeatedly dissolved indry benzene and concentrated until no thionyl chloride remains to yield10.8 g of the title compound (7) as a waxy solid.

Step E: Ethyl 4-(2-(11-carbomethoxyundecanoylamino)-phenoxy)butyrate (8)

To a stirred, ice-cold solution of 0.89 g (4.0 mM) amine (4) and driedtriethylamine (1.2 mL) in dry ether (40 mL) is added dropwise over ca. 4minutes a solution of acid chloride (7) (1.04 g, 4.6 mM) in 20 mL of dryether. The resultant mixture is allowed to stir cold for 20 minutes, andthen at room temperature overnight. After filtering off thetriethylamine hydrochloride, the ether filtrate is concentrated in vacuoand the residue chromatographed on an 82 g silica gel column using 20%ethyl acetate/hexane as eluant to give 1.49 g (85%) of (8) as a waxysolid.

The ether/triethylamine in the above reaction may be replaced bymethylene chloride/pyridine with similar results. The same compound mayalso be prepared via direct coupling of acid (6) with the same amineusing common coupling reagents, such asdicyclohexylcarbodiimide/N,N-dimethylaminopyridine, and the like.

Step F: 4-(2-(11-Carboxyundecanoylamino)phenoxy)-butyric acid (9)

To a stirred solution of (8) (1.0 g, 2.22 mM) in methanol (100 mL) isadded 1 mL of water followed by dropwise addition of 2.5 N sodiumhydroxide solution (4.0 mL). The walls of the reaction flask are rinseddown with 10 mL of methanol and the mixture is stirred under a nitrogenatmosphere until TLC analysis shows no ester (mono- or di-) remaining.The methanol is removed in vacuo, the residue taken up in 100 mL ofwater, stirred for solution, filtered (20 mL water rinses), and thestirred filtrate acidified dropwise with 2 N hydrochloric acid.Filtration of the resultant precipitate followed by copious waterwashing and drying gave 0.87 g (96%) of (9) as a chalk-like white solid.The compound was one component by TLC (silica gel, the eluant was 10 mLof 2% methanol in methylene chloride containing 4 drops of glacialacetic acid). mp 128.5-130° C. uncorr.

Microanalysis: Calc.: C, 64,84; H, 8.16; N, 3.44. Found: C, 64,90; H,8.34; N, 3.33.

Step G: Ethyl 4-(2-Amino-3-methylphenylthio)butyrate (11)

To a stirred deaerated (N₂) solution of 2-aminothiophenol (10) (1.25 g.,10 mM) and ethyl 4-bromobutyrate (2.14 g., 11 mM) in 40 mL. of dry1,2-dimethoxyethane is added 8.3 g. of solid ground anhydrous potassiumcarbonate, the resultant mixture deaerated 3× under nitrogen and allowedto stir at room temperature until TLC analysis indicates the reaction iscomplete. The filtered mixture is then concentrated and the residueflash chromatographed on silica gel (85 g.) using 15% ethylacetate/hexane as eluant to give 1.8 g. of (11) as a pale tan oil.

Step H: 4-(2-(11-Carboxyundecanoylamino)phenylthio)butyric acid (13)

When amine (11) is acylated with acid chloride (7) as per procedure Step(E), and the resultant diester (ethyl4-(2-(11-carbomethoxyundecanoylamino)phenylthio)butyrate 12 ishydrolyzed in Step I as per procedure (F), the title compound, 13 m.p.113.5-115° C. is obtained.

The following representative compounds in this series were additionallymade by the procedures outlined above:

14) 4-(2-(9-Carboxynonanoylamino)phenoxy)butyric acid, m.p. 121.5-124.5°C.

15) 4-(2-(10-Carboxydecanoylamino)phenoxy)butyric acid, m.p. 110-111.5°C.

16) 4-(2-(12-Carboxydodecanoylamino)phenoxy)butyric acid, m.p. 116-119°C.

17) 4-(2-(13-Carboxytridecanoylamino)phenoxy)butyric acid, m.p.128-129.5° C.

18) 4-(2-(15-Carboxypentadecanoylamino)phenoxy)butyric acid, m.p.121-125° C.

19) 5-(2-(11-Carboxyundecanoylamino)phenoxy)valeric acid, m.p.112-113.5° C.

20) 4-(2-(11-Carboxyundecanoylamino)-3-methylphenoxy)butyric acid, m.p.134.5-136.5° C.

21) 4-(2-(11-Carboxyundecanoylamino)-4-methylphenoxy)butyric acid, m.p.99.5-100.5° C.

22) 4-(2-(11-Carboxyundecanoylamino)-5-methylphenoxy)butryic acid, m.p.109.5-113° C.

Step J: Benzyl 2-Nitrophenyl Ether (23)

When 2-nitrophenol (1) is reacted with benzylbromide under theconditions of Step A the title ether (23) is obtained as a golden oil.

Step K: Benzyl 2-Aminophenyl Ether (24)

A solution of benzyl 2-nitrophenyl ether (23) (1.15 g., 5.0 mM) inethanol (25 mL) saturated with anhydrous ammonia is stirred under ahydrogen atmosphere (40 p.s.i.) with Raney Nickel (2 g.) until TLCanalysis indicates the absence of starting nitro compound. The filteredmixture is freed of excess ammonia by bubbling in anhydrous nitrogen.Removal of ethanol via vacuum distillation at room temperature yields1.0 g. of title compound (24) as a deep colored crust, which was usedas-is in the next reaction. This compound may also be obtained viacareful reduction in ethanol or ethyl acetate using palladium on carbonas catalyst, but can be accompanied by slight,over-reduction if notmonitored.

Step L: N-Trifluoroacetyl 2-Benzyloxvaniline (25)

To a stirred, near solution of amine (24) (5.0 mM) in dry diethyl ether(30 mL) is added anhydrous sodium carbonate (6.0 g., 57 mM) and theresultant mixture cooled in an ice-water bath. Trifluoroacetic anhydride(1.5 mL, 10.6 mM) is added dropwise to this cold mixture over 2 minutes,the color changing to a yellowish red. After 2 hours the cooling-bath isremoved and the mixture allowed to stir at ambient temperaturesovernight. After filtering, the filtrate is concentrated in vacuo andthen pumped to yield 1.3 g. of the title compound (25) as a pale tan(with some reddish-brown color around the edges) crust.

Step M: N-Methyl-2-Benzyloxyaniline (27)

A well-stirred solution of (25) (0.295 g., 1.0 mM), methyl iodide (0.25mL, 4.0 mM) and anhydrous acetone (5.0 ml) is set in an oil-bathpreviously heated to 59° C., and kept for 2 minutes. Powdered anhydrouspotassium hydroxide (0.225 g., 4.0 mM) is added all at once, and thebath temperature allowed to rise to 65° C. Clumping-up of some of theKOH is observed. After 15 additional minutes, the reaction mixture isremoved from the bath, allowed to cool, and the volatiles removed.Methanol (7 mL) is added with stirring to the residue ofN-Methyl-N-trifluoroacetyl-2-benzyloxyaniline (26) obtained, followed bywater (1 mL), and methanol (2 mL) (to wash down the sides). Afterstirring overnight at ambient temperatures, the methanol is removed invacuo, the residue distributed between ether and water, separated, theorganic layer washed with additional water, saturated sodium chloridesolution, and dried over sodium sulfate. Concentration of the filteredether solution gives the title compound (27) (0.212 g.) as an oil. NMR,MS, and TLC indicate little, if any, dimethyl compound.

Step N: N-(11-(Carbomethoxy)undecanoyl)-N-Methyl-2-Benzyloxyaniline (28)

To a stirred ice-cold solution of (27) (0.21 g., 1.0 mM) in driedmethylene chloride (10 mL) containing anhydrous pyridine (0.3 mL) isadded (7) (0.27 g., 1.03 mM), dissolved in 5 methylene chloride (5 mL),dropwise over 1 minute (some methylene chloride used as a rinse). Afterstirring cold for 30 minutes, the mixture is allowed to stir at ambienttemperature for completion of the reaction. The reaction mixture iswashed 1× with , 1N HCL, dried (Na₂ SO₄) and filtered. Flashchromatography (silica gel, 20% ethyl acetate/hexane as eluant) of theresidue obtained gives the title compound (28) (0.33 g) as a colorlessoil.

Step O: N-(11-(Carbomethoxy)undecanoyl)-N-Methyl-2-Hydroxy aniline (29)

A solution of (28) (0.11 g., 0.25 mM) in methanol (11 mL) containing 10%palladium on carbon (30 mg.) is shaken in a 40 p.s.i. hydrogenatmosphere until no (V) remained (TLC analysis). The filtered solutionwas then concentrated in vacuo to give the title compound (29), usedimmediately in step P.

Step P: Ethyl4-(2-N-(11-Carbomethoxyundecanoyl)-N-(methyl)-amino)phenoxybutyrate (30)

To a stirred solution of (29) (0.087 g., 0.25 mM) and ethyl4-bromobutyrate (0.115 mL, 0.80 mM) in anhydrous acetone (10 mL) isadded anhydrous ground potassium carbonate (0.45 g., 3.2 mM) and theresultant mixture heated under gentle reflux undera nitrogen atmospherefor 24 hours. The mixture is cooled, filtered, and concentrated, and theresidue flash chromatographed (silica gel; 20% ethyl acetate/hexaneeluant) to give 80 mg. of the title compound (30) as a colorless oil.

Step Q: 4-(2-N-(11-Carboxyundecanoyl)-N-(methyl)-amino)-phenoxybutyricAcid (31)

When (30) (0.055 g., 0.118 mM) is hydrolyzed as per its N-desmethylanalog (Step F, supra), and the resultant oil obtained afteracidification is extracted with methylene chloride, there is obtainedthe title compound (31), (51 mg.), as a colorless oil.

Step R: Ethyl 4-(2-(11-Bromoundecanoylamino)phenoxy)-butyrate (32)

To a solution of (4) (2.60 g., 11 mM) and 11-bromoundecanoic acid (2.65g., 10 mM) in anhydrous methylene chloride (90 mL) is added4-(dimethylamino)pyridine (1.22 g., 10 mM) followed byN,N'-dicyclohexylcarbodiimide (2.3 g., 11 mM) (4×5 mL ofmethylenechloride rinses). Precipitation of dicyclohexylurea (DCU)begins within 4 minutes. When TLC analysis indicates the reaction iscomplete, the mixture is filtered, the filtrate concentrated in vacuoand the residue extracted with ether. The combined ether extracts arewashed 1× with 1N hydrochloric acid, 1× saturated sodium chloridesolution, dried (Na₂ SO₄) and concentrated to a residue which isstirred, filtered, and concentrated alternately with ether and methylenechloride until all DCU is removed. Concentration of the final solutionyields the title product (32) (2.35 g.) as an oil that goes readily to awaxy solid.

Attempted purification of an earlier run via column chromatography(silica gel;20% ethyl acetate/hexane as eluant) gave an impure productof greatly diminished yield.

Step S: Diethyl10-(N-((2-(3-Carboethoxy)propyloxy)-phenyl)carboxamido)decylphosphonate(33)

A stirred mixture of (32) (0.235 g., 0.5 mM) and triethyl phosphite(TEP) (0.3 mL) is heated at 180° C. (bath temperature) under a nitrogenatmosphere for 8 hours, cooled, excess TEP removed in vacuo, and theresidue flash chromatographed (Silica gel; ethyl acetate as eluant) toyield product 33 (0.13 g.) as a clear colorless oil.

Step T:

Cleavage of the phosphonate ester (33) using bromotrimethylsilane(procedure of J.C.S. Chem. Comm. p.739 (1979) yields10-(N-((2-(3-(Carboethoxy)-propyloxy)phenyl carboxamido)decylphosphonicacid (34).

Step U:

Further hydrolysis of (34) using the procedure of Example (F) aboveyields the corresponding di-acid,10-(N-((2-(3-Carboxy)propyloxy)phenyl)carboxamido)-decylphosphonic acid(35).

Step V:10-(N-((2-(3-Carboethoxy)propyloxy)phenyl)-carboxamido)decaneisothiouroniumbromide (36)

A stirred solution of (32) (0.047 g., 0.1 mM) in ethanol (2 mL) isreacted with thiourea (0.010 g., 0.13 mM) under the same conditions as(in Step W.). Concentration of the reaction mixture yields the titlecompound (36) (contaminated with a small amount of thiourea) whichslowly solidifies in crystalline circles on standing. Stirring withdried chloroform followed by filtration and concentration yields theproduct as a thick wax.

Step W: Sodium10-(N-((2-(3-Carboethoxy)propyloxy)-phenyl)carboxamido)decanethiosulfate(37)

To a stirred solution of (32) (0.047 g., 0.1 mM) in ethanol (2.0 mL) isadded water (10 drops, slowly) followed by sodium thiosulfate (0.035 g.,0.14 mM), and the reaction mixture heated in an oil-bath (bathtemperature ca. 90° C.) under a nitrogen atmosphere until TLC analysisindicated no starting bromo compound. The cooled mixture was thenconcentrated to remove the ethanol and water yielding a white crust.Extraction of this crust with chloroform, followed by filtration frominorganics, yielded product (37) (49 mg.) as a glaze which goes withtime to a waxy solid. This product has appreciable water solubility.

Oxidation of (36) or (37) as per the analogous procedures in J. S.Showell et al., J. Org. Chem 27 (1962) 2853 or C. Ziegler et al J. Org.Chem. (1951) 621) yields the corresponding sulfonic acid (38).

Step X: Ethyl 4-(2-Nitropyrid-3-yloxy)butyrate (40)

This compound was prepared from ethyl 4-bromobutyrate 2 and2-nitro-3-pyridinol (39) via the procedure of Step (A), supra. Followingflash chromatography (silica gel; 1.5% methanol/methylene chlorideeluant) a dilute sodium bicarbonate wash of an ether solution of theproduct was necessary to remove traces of starting phenol. The product(40) was obtained in 76% yield as a pale yelow oil.

Step Y: Ethyl 4-(2-Aminopyrid-3-yloxy)butyrate (41)

This compound was prepared via reduction of (40) as per the procedure ofstep (B), above. The amine (41) was obtained as a waxy solid.

Step Z: Ethyl4-(2-(11-Carbomethoxyundecanoylamino)pyrid-3-yloxy)butyrate (42)

When (41) and (7) are reacted as per the procedure of step (E), above,the title compound (42) is obtained. Hydrolysis will yield thecorresponding di-acid(4-(2-(11-Carboxyundecanoylamino)pyrid-3-yloxy)butyric acid (43).

Step AA: N-(11-Carbomethoxyundecanoyl)-2-hydroxyaniline (44)

To a stirred near solution of 2-aminophenol (0.24 g, 2.2 mM) inanhydrous methylene chloride (25 mL) was added dry pyridine (0.66 mL)and the mixture cooled in an ice-water bath. A solution of (7) (0.525 g,2.0 mM) in methylene chloride (2 mL) was added over 1 minute (2×1.5 mLmethylene chloride rinses), and the mixture allowed to stir cold. After30 minutes the bath was removed. After stirring overnight at ambienttemperatures, the mixture was filtered, the solvents removed in vacuo,and the residue pumped to remove all traces of pyridine. The product,(44) was used as is in subsequent steps.

Step BB: 4-(2-(11-Carbomethoxyundecanoylamino)phenoxy)-butyronitrile(45)

When (44) and 4-bromobutyronitrile are reacted under the conditions ofstep (A), above, (45) is obtained as a waxy solid. Conversely, reacting(44) with ethyl 4-bromobutyrate as in step (A) yields (8).

Step CC: 4-(2-(11-Carbomethoxyundecanoylamino)phenoxy)-butyramide (46)

To a stirred solution of (45) (11 mg, 0.027 mM) in methylene chloride (3mL) is added activated manganese dioxide (100 mg) and the resultantsuspension allowed to stir stoppered at room temperature. After a fewdays some additional methylene chloride and manganese dioxide (100 mg)are added and the reaction allowed to continue. This is repeated oneadditional time. When TLC analysis shows no nitrile remains the mixtureis filtered, the catalyst washed well with fresh methylene chloride, andthe filtrate concentrated to yield the title product, (46) as a waxysolid.

The above new isolated, purified compounds had NMR and Mass spectraconsistent with their assigned chemical structures. All melting pointswere taken on an A.O. Spencer hot stage and are uncorrected.

CHAPTER 4 Example 1

17β-Benzoyl-Androst-3,5-diene-3-Carboxylic Acid

The title compound is made by reacting17β-carbomethoxy-androst-3,5-diene-3-protected carboxylic acid in e.g.,THF, with phenyl magnesium bromide under standard Grignard conditions.Standard workup procedure yields the title. compound, m.p.222-225° C.

Reference Example 1

Synthesis of 4-(4-isobutylbenzyloxy)-2,3-dimethylbenzaldehyde ##STR68##

A mixture of 4-hydroxy-2,3-dimethylbenzaldehyde (220 mg),4-isobutylbenzyl bromide (341 mg), potassium carbonate (1.38 g) andethyl methyl ketone (10 ml) was refluxed for 6 hrs. After cooling, thereaction mixture was diluted with ethyl acetate, the solution was washedwith di1 hydrochloric acid, water, successively, dried and evaporated.The residue was purified by column chromatography on silica gel(hexane:EtOAc=10:1) to give the title compound (383 mg) having thefollowing physical data:

TLC: Rf 0.48 (hexane:EtOAc=5:1); NMR: δ7.64 (1H, d), 7.32 (1H, d), 7.16(1H, d), 5.12 (2H, s), 2.60 (3H, s), 2.48 (2H, d), 2.24 (3H, s),1.94-1.80 (1H, m), 0.90 (6H, d).

Reference Example 2

Synthesis of 4-(4-isobutylbenzyloxy)-2,3-dimethylbenzoic acid ##STR69##

A solution of the aldehyde prepared in reference example 1 (380 mg) inacetone (5 ml) was cooled with ice. To the solution, Jones' reagent(2.67 N; 2 ml) was dropped and allowed to stand. The solution wasstirred for 1.5 hrs at room temperature. The reaction was stopped byaddition of isopropyl alcohol. The crystals deposited were washed withhexane, dried and purified by column chromatography on silica gel(hexane-EtOAc) to give the title compound (328 mg) having the followingphysical data: TLC: Rf 0.36 (hexane:EtOAc=2:1); NMR: δ7.80 (1H, d), 7.33(1H, d), 7.15 (1H, d), 6.90 (1H, d), 5.09 (2H, s), 2.58 (3H, s), 2.48(2H, d), 2.26 (3H, s), 0.91 (6H, d).

Reference Example 3

Synthesis of4-[2-[4-(4-isobutylbenzyloxy)-2,3-dimethylbenzoylamino]phenoxy]butanoicacid ethyl ester ##STR70##

Oxalyl chloride (2 ml) was dropped to a solution of the carboxylic acidprepared in reference example 2 (325 mg) in methylene chloride (2 ml).The solution was stirred for 1 hr and evaporated. To an ice-cooledmixture of ethyl 4-(2-aminophenoxy)-butanoate (232 mg), pyridine (1 ml)and methylene chloride (15 ml), the above solution was dropped. Themixture was stirred for 30 mins at the same temperature and for 1 hr atroom temperature. The reaction solution was washed with water, dried andevaporated. The residue was purified by column chromatography on silicagel (hexane:EtOAc=5:1) to give the title compound (383 mg) having thefollowing physical data:

TLC: Rf 0.5 (hexane:EtOAc=3:1); NMR: δ 8.58-8.48 (1H, m), 8.05 (1H, s),7.34 (H, d), 7.16 (1H, d), 7.08-6.96 (2H, m), 6.90-6.80 (2H, m), 5.07(2H, s) 4.14-3.96 (4H, m), 2.49 (2H, d), 2.44 (3H, s), 1.18 (3H, t),0.91 (6H, d).

Reference Example 4

Synthesis of4-[2-[4-(4-isobutylbenzyloxy)-2,3-dimethylbenzoylamino]phenoxy]butanoicacid ##STR71##

1N aq. Solution of lithium hydroxide (3 ml) was added to a solution ofthe ester prepared in Reference Example 3 (380 mg) in dimethoxyethane (8ml). The mixture was stirred for 30 mins at 50° C. After reaction, thesolution was neutralized with dil. hydrochloric acid and was extractedwith ethyl acetate. The extract was dried and evaporated. The residueobtained was recrystallized from hexane to give the title compound (317mg) having the following physical data:

TLC: Rf 0.26 (hexane:EtOAc=1:1): mp: 143° C.

Reference Example 5

By the similar procedure as reference examples 1, 2, 3 and 4, thefollowing compound was made,4-[2-[4-[1-(4-isobutylphenyl-)ethoxy)-2,3-dimethylbenzoylamino]phenoxy]butanoicacid, having the structural formula: ##STR72## in which the Rf value is0.37 (hexane:EtOAc=1:1), and the mass spectrum exhibited m/z values of503, 345.

Reference Example 6

(-)-4-[2-(4-[1-(4-isobutylphenyl)ethoxy]-2,3-dimethylbenzoylaminophenoxy]butanoic acid

The compound prepared above in reference example 5, (403 mg) andcinchonidine (2.36 g) were dissolved into acetone (70 ml) with heating.The solution was allowed to stand to give white crystals. The crystalswere gathered by filtration and purified by recrystallization fromacetone four times. The white crystals obtained were dissolved intochloroform. The solution was wahsed with dil. hydrochloric acid. Theoily layer was washed with water, dried and evaporated to give the titlecompound having the following physical data:

Appearance: white crystal; Optical angle of rotation: [a]_(D) -39.6°(c=1, CHCl₃)

Reference Example 7

Sodium salt of(-)-4-[2-(4-[1-(4-isobutylphenyl)-ethoxy]-2,3-dimethylbenzoylamino)phenoxy]butanoicacid

The compound prepared in Reference Example 6 was dissolved intomethanol. The equivalent molar of an aq. Sodium hydroxide solution wasadded and evaporated to give the title compound having the followingdata: IR: ν 3050, 1750, 1580, 1560, 1510, 1445, 1260, 1090, 1020, 740cm-1.

FORMULATION EXAMPLE

The following components are admixed in conventional method and punchedout to obtain 100 tablets each containing 50 mg of active ingredient.

    ______________________________________                                        4-[2-[4-[1-(4-isobutylphenl)ethoxy)-                                                                   5     g                                                2,3-dimethylbenzoylamino)phenoxy]                                             butanoic acid                                                                 Cellulose calcium gluconate 0.2 g                                             (disintegrating agent)                                                        Magnesium stearate 0.1 g                                                      (lubricating agent)                                                           Microcrystaline cellulose 4.7 g                                             ______________________________________                                    

What is claimed is:
 1. A method of treating prostatic cancer in patientswho are in need of such treatment comprising the step of administeringto such patients enhanced therapeutically effective amounts of the5α-reductase inhibitor finasteride or a pharmaceutically acceptableester or salt thereof in combination with the antiandrogen casodex.
 2. Amethod according to claim 1 of treating prostatic cancer in patients whoare in need of such treatment comprising the step of administering tosuch patients enhanced therapeutically effective amounts of the5α-reductase inhibitor finasteride or a pharmaceutically acceptableester or salt thereof, in combination with the antiandrogen casodex,wherein the combination is more effective than the use of either the5α-reductase inhibitor or antiandrogen by itself.
 3. A pharmaceuticalcomposition for the treatment of prostatic cancer comprising enhancedtherapeutically effective amounts of the 5α-reductase inhibitorfinasteride and the antiandrogen casodex.